The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3.
ClinVar Genomic variation as it relates to human health
NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005343.4(HRAS):c.34G>A (p.Gly12Ser)
Variation ID: 12602 Accession: VCV000012602.63
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 534289 (GRCh38) [ NCBI UCSC ] 11: 534289 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 16, 2015 Oct 8, 2024 Apr 3, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005343.4:c.34G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005334.1:p.Gly12Ser missense NM_176795.5:c.34G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_789765.1:p.Gly12Ser missense NM_001130442.3:c.34G>A NP_001123914.1:p.Gly12Ser missense NM_001318054.2:c.-286G>A 5 prime UTR NC_000011.10:g.534289C>T NC_000011.9:g.534289C>T NG_007666.1:g.6262G>A LRG_506:g.6262G>A LRG_506t1:c.34G>A LRG_506p1:p.Gly12Ser P01112:p.Gly12Ser - Protein change
- G12S
- Other names
-
p.G12S:GGC>AGC
NM_005343.3(HRAS):c.34G>A
- Canonical SPDI
- NC_000011.10:534288:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HRAS | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh37 |
12 | 723 | |
| LRRC56 | - | - |
GRCh38 GRCh38 GRCh37 |
346 | 1057 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (24) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000013435.78 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2014 | RCV000013436.34 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2014 | RCV000022796.15 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2021 | RCV000081295.29 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000149828.10 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000417494.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2014 | RCV000029209.16 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000425542.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432342.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432945.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440297.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000430608.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000443940.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000435163.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440863.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440993.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000445039.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000422253.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000430725.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000433576.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000438022.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 19, 2016 | RCV001813185.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2020 | RCV001257537.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 8, 2023 | RCV002453256.10 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2022 | RCV003156059.8 |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000419709.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000420366.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000422656.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000423310.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000424896.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000427772.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000430011.9 | |
|
HRAS-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jan 29, 2024 | RCV003398496.6 |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000432984.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000440237.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2014 | RCV000487471.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255689.9 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV003450635.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2023 | RCV003450636.1 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 03, 2017)
|
reviewed by expert panel
Method: curation
|
Costello syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616364.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a … (more)
The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3. (less)
|
|
|
Pathogenic
(Apr 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000263952.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 26, 2017 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227361.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Jul 30, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062131.5
First in ClinVar: May 03, 2013 Last updated: Dec 26, 2017 |
Comment:
The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep … (more)
The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 13
|
|
|
Pathogenic
(May 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362310.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three … (more)
Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423659.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Comment:
[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) … (more)
[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
|
|
|
Pathogenic
(Feb 16, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603969.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
Comment:
The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr … (more)
The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72. (less)
|
|
|
Pathogenic
(Oct 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
de novo
|
Baylor Genetics
Accession: SCV001520829.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Oct 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002025029.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000288856.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002615093.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution … (more)
The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Centre for Human Genetics
Accession: SCV005199936.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Comment:
The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, … (more)
The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. (less)
Number of individuals with the variant: 2
Secondary finding: no
|
|
|
Pathogenic
(Jun 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000263052.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
none provided (present)
Age: 0-9 years
Sex: male
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
failure to thrive, feeding issues, multiple papillomata, skeletal anomalies, foot deformities, developmental delay (present)
Age: 0-9 years
Sex: male
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
clinical features of Costello Syndrome (present) , subglottic stenosis (present)
Age: 0-9 years
Sex: female
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
none provided (present)
Age: 10-19 years
Sex: male
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
dysmorphic at birth, developed seizures, atrial septal defect, coarctation of the aorta, hypotonia, gastroesophageal refulx disease, developmental delay (present)
Age: 0-9 years
Sex: male
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
coarse facial features, macroglossia, failure to thrive, redundant skin on plams, atrial tachycardia (present)
Age: 0-9 years
Sex: female
Observation 7:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Coarse facial features (present) , Congestive heart failure (present) , Feeding tube (present) , Moderate to profound mental retardation (present) , Polyhydramnios in utero (present)
Age: 10-19 years
Sex: male
Observation 9:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Observation 10:
Number of individuals with the variant: 1
Clinical Features:
Coarse facial features (present) , Deep palmar creases (present) , Redundant skin on scalp (present) , Pulmonic stenosis (present)
Age: 0-9 years
Sex: male
Observation 11:
Number of individuals with the variant: 1
Clinical Features:
Coarse facies (present) , Hydrocephalus (present) , Hypertrophic cardiomyopathy (present) , Growth hormone deficiency (present) , Scoliosis (present) , Papilloma (present)
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781527.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
|
|
Pathogenic
(Jul 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
COSTELLO SYNDROME
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996166.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar … (more)
This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167662.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Secondary finding: no
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|
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Pathogenic
(Nov 29, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000207842.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 17, 2019 |
Comment:
Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey … (more)
Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669) (less)
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Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
unknown
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976682.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS1, PM1, PM2, PM5, PP2, PP3, PP5
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|
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058657.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Delayed myelination (present) , Downslanted palpebral fissures (present) , Abnormal facial shape (present) , Failure to thrive (present) , Feeding difficulties (present) , Depressed nasal … (more)
Delayed myelination (present) , Downslanted palpebral fissures (present) , Abnormal facial shape (present) , Failure to thrive (present) , Feeding difficulties (present) , Depressed nasal bridge (present) , Frontal bossing (present) , Full cheeks (present) , High, narrow palate (present) , Hypertelorism (present) , Generalized hypotonia (present) , Abnormality of limbs (present) , Low-set ears (present) , Relative macrocephaly (present) , Mild short stature (present) , Short chin (present) , Myopathy (present) , Short stature (present) (less)
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Pathogenic
(Mar 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059320.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Dec 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060955.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
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Pathogenic
(Jun 07, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002568185.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PS2 PS3 PS4 PM2 PM5
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Pathogenic
(Sep 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580200.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS2, PS4, PM5, PM2_SUP
|
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Mar 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817295.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations … (more)
Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
unknown
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845220.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Abnormal pinna morphology (present) , Abnormal thorax morphology (present) , Arthrogryposis-like hand anomaly (present) , Camptodactyly (present) , Hepatoblastoma (present) , Narrow chest (present) , … (more)
Abnormal pinna morphology (present) , Abnormal thorax morphology (present) , Arthrogryposis-like hand anomaly (present) , Camptodactyly (present) , Hepatoblastoma (present) , Narrow chest (present) , Paroxysmal atrial tachycardia (present) , Pectus excavatum (present) (less)
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Pathogenic
(Dec 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037370.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The … (more)
The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879) (less)
Clinical Features:
Abnormal heart morphology (present) , Multifocal atrial tachycardia (present) , Pleural effusion (present) , Respiratory insufficiency (present) , Respiratory insufficiency (present) , Immunodeficiency (present) , … (more)
Abnormal heart morphology (present) , Multifocal atrial tachycardia (present) , Pleural effusion (present) , Respiratory insufficiency (present) , Respiratory insufficiency (present) , Immunodeficiency (present) , Hypotonia (present) , Global developmental delay (present) , Failure to thrive (present) (less)
Age: 0-9 years
Sex: female
Tissue: DNA
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|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171305.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. … (more)
The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Epidermal nevus
Affected status: yes
Allele origin:
somatic
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004176909.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi … (more)
An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.34G>A (p.Gly12Ser) variant is classified as pathogenic. (less)
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Pathogenic
(Apr 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801624.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in … (more)
The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome. (less)
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Pathogenic
(Jul 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV000680007.2
First in ClinVar: Dec 26, 2017 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome and congenital myopathy with excess of muscle spindles (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Rasopathy
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000196672.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Comment:
Variant classified using ACMG guidelines
|
|
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Pathogenic
(Apr 01, 2014)
|
no assertion criteria provided
Method: literature only
|
NEVUS, WOOLLY HAIR, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000574678.2
First in ClinVar: May 01, 2017 Last updated: Dec 15, 2018 |
Comment on evidence:
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more)
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
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Pathogenic
(Apr 01, 2014)
|
no assertion criteria provided
Method: literature only
|
COSTELLO SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000033682.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more)
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
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Pathogenic
(Apr 01, 2014)
|
no assertion criteria provided
Method: literature only
|
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000033683.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more)
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
|
|
|
Pathogenic
(Apr 01, 2014)
|
no assertion criteria provided
Method: literature only
|
EPIDERMAL NEVUS WITH UROTHELIAL CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000044085.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more)
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
|
|
|
Pathogenic
(Apr 01, 2014)
|
no assertion criteria provided
Method: literature only
|
NEVUS SEBACEOUS, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000051855.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the … (more)
Costello Syndrome In 3 Japanese and in 4 Italian patients with Costello syndrome (218040), Aoki et al. (2005) identified a germline 34G-A transition in the HRAS gene that caused a gly12-to-ser (G12S) amino acid substitution. Kerr et al. (2006) analyzed the HRAS gene in 43 patients with a clinical diagnosis of Costello syndrome and identified mutations in 37 (86%); G12S was the most common mutation, found in 30 of the 37 mutation-positive patients. Zampino et al. (2007) identified the G12S mutation in 8 of 9 unrelated patients with Costello syndrome. By analyzing the flanking genomic region, the authors determined that all patients had de novo mutations inherited from the father. There was an advanced age at conception in affected fathers transmitting the mutation. The phenotype was homogeneous. In a male infant with severe Costello syndrome, Lo et al. (2008) identified the G12S mutation in the HRAS gene. The patient had persistent neonatal hypoglycemia, hypocalcemia, right ventricular hypertrophy, and enlarged kidneys. He required pyloromyotomy for pyloric stenosis and inguinal hernia repair at age 3 months. He had complex upper and lower airway obstruction with a floppy tongue, narrow subglottic opening, and tracheobronchomalacia, requiring a tracheostomy with intermittent ventilatory support. Deterioration of his respiratory function led to the discovery of a pulmonary rhabdomyosarcoma, and he died at 2.25 years of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12S mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a phenotypic variant of Costello syndrome. The patient, originally reported by Selcen et al. (2001), died at age 14 months of cardiorespiratory failure. He had generalized muscle weakness, areflexia, joint contractures, and clubfeet. Epidermal Nevus and Urothelial Cancer, Somatic Hafner et al. (2011) reported a 49-year-old man who had widespread mosaicism for a G12S mutation present in tissues derived from endoderm, ectoderm, and mesoderm, suggesting an embryonic mutation. The patient presented at 49 years of age with widespread congenital epidermal nevus (162900). At 19 years of age a urothelial cell carcinoma was detected in the bladder, and 2 new tumors were identified at 48 years of age. At age 49 a single metastatic lesion was identified in lung. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12S mutation in 3 (5%) of 65 nevus sebaceous tumors (see 162900). Woolly Hair Nevus, Somatic By paired whole-exome sequencing of DNA in affected tissue and blood from 2 unrelated girls with woolly hair nevus (see 162900), Levinsohn et al. (2014) identified heterozygosity for a somatic G12S mutation in the HRAS gene in both individuals. Analysis of hair bulbs from straight and curly patient hair confirmed that the G12S mutation was present in curly hair only. There was no evidence for loss of heterozygosity or a secondary somatic mutation, suggesting that HRAS mutation alone is sufficient to cause woolly hair nevus. (less)
|
|
|
Pathogenic
(Apr 30, 2019)
|
no assertion criteria provided
Method: research
|
Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432254.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 01, 2020)
|
no assertion criteria provided
Method: provider interpretation
|
Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434363.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809092.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955792.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967870.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(Oct 14, 2021)
|
no assertion criteria provided
Method: research
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University
Accession: SCV003844076.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Clinical Features:
Increased nuchal translucency (present) , Cystic hygroma (present)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics, Centre for Human Genetics
Accession: SCV004190105.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 6
Secondary finding: no
|
|
|
Pathogenic
(Jan 29, 2024)
|
no assertion criteria provided
Method: clinical testing
|
HRAS-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004104104.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in … (more)
The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic. (less)
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Pancreatic adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506475.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Acute myeloid leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506477.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Gastric adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506474.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant neoplasm of body of uterus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506472.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Adenoid cystic carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506473.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple myeloma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506476.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Glioblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506478.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Carcinoma of esophagus
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506479.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506483.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Uterine carcinosarcoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506485.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Thyroid tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506480.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Papillary renal cell carcinoma, sporadic
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506481.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Transitional cell carcinoma of the bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506484.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506482.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Prostate adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506486.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of uterine cervix
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506487.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506491.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506488.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506489.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Myelodysplastic syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506490.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Hepatocellular carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506493.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Ovarian serous cystadenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506492.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Nasopharyngeal neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506494.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell carcinoma of the skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000506495.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Dec 18, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805105.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
|
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Comment:
Comment:
The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Comment:
Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Comment:
The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic.
Comment:
This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic.
Comment:
Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669)
Comment:
PS1, PM1, PM2, PM5, PP2, PP3, PP5
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS2 PS3 PS4 PM2 PM5
Comment:
Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879)
Comment:
The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.34G>A (p.Gly12Ser) variant is classified as pathogenic.
Comment:
The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome and congenital myopathy with excess of muscle spindles (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant classified using ACMG guidelines
Comment:
The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3.
Comment:
The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Comment:
Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Comment:
The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The HRAS c.34G>A(p.Gly12Ser) variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic.
Comment:
This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic.
Comment:
Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669)
Comment:
PS1, PM1, PM2, PM5, PP2, PP3, PP5
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS2 PS3 PS4 PM2 PM5
Comment:
Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879)
Comment:
The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Comment:
An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.34G>A (p.Gly12Ser) variant is classified as pathogenic.
Comment:
The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome and congenital myopathy with excess of muscle spindles (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant classified using ACMG guidelines
Comment:
The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| HRAS-Related Costello Syndrome. | Adam MP | - | 2023 | PMID: 20301680 |
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
| Costello syndrome: Clinical phenotype, genotype, and management guidelines. | Gripp KW | American journal of medical genetics. Part A | 2019 | PMID: 31222966 |
| ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
| Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics. | Gripp KW | Clinical genetics | 2017 | PMID: 28139825 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences. | Gripp KW | American journal of medical genetics. Part A | 2015 | PMID: 25914166 |
| Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi. | Levinsohn JL | The Journal of investigative dermatology | 2014 | PMID: 24129065 |
| Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome. | Wey M | Biochemistry | 2013 | PMID: 24224811 |
| Craniofacial and dental malformations in Costello syndrome: A detailed evaluation using multi-detector row computed tomography. | Takahashi M | Congenital anomalies | 2013 | PMID: 23751039 |
| Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. | Groesser L | Nature genetics | 2012 | PMID: 22683711 |
| Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val. | Burkitt-Wright EM | American journal of medical genetics. Part A | 2012 | PMID: 22495892 |
| C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome. | Klüppel M | European journal of human genetics : EJHG | 2012 | PMID: 22317973 |
| HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. | Hafner C | The New England journal of medicine | 2011 | PMID: 22087699 |
| HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. | Niihori T | Journal of human genetics | 2011 | PMID: 21850009 |
| Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome. | Gripp KW | American journal of medical genetics. Part A | 2011 | PMID: 21834037 |
| Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation. | Girisha KM | American journal of medical genetics. Part A | 2010 | PMID: 20979192 |
| Enhanced human brain associative plasticity in Costello syndrome. | Dileone M | The Journal of physiology | 2010 | PMID: 20660566 |
| Recurring G12S mutation of HRAS in a Chinese child with Costello syndrome with high alkaline phosphatase level. | Zhang H | Biochemical genetics | 2009 | PMID: 19669404 |
| Costello syndrome H-Ras alleles regulate cortical development. | Paquin A | Developmental biology | 2009 | PMID: 19371735 |
| Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism. | Sol-Church K | American journal of medical genetics. Part A | 2009 | PMID: 19206176 |
| Partially correlated thin annular sources: the scalar case. | Gori F | Journal of the Optical Society of America. A, Optics, image science, and vision | 2008 | PMID: 18978862 |
| Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? | Gripp KW | American journal of medical genetics. Part A | 2008 | PMID: 18247425 |
| Severe neonatal manifestations of Costello syndrome. | Lo IF | Journal of medical genetics | 2008 | PMID: 18039947 |
| Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. | van der Burgt I | Journal of medical genetics | 2007 | PMID: 17412879 |
| Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. | Zampino G | Human mutation | 2007 | PMID: 17054105 |
| Somatic mosaicism for an HRAS mutation causes Costello syndrome. | Gripp KW | American journal of medical genetics. Part A | 2006 | PMID: 16969868 |
| Recurring HRAS mutation G12S in Dutch patients with Costello syndrome. | van Steensel MA | Experimental dermatology | 2006 | PMID: 16881968 |
| Paternal bias in parental origin of HRAS mutations in Costello syndrome. | Sol-Church K | Human mutation | 2006 | PMID: 16835863 |
| Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. | Kerr B | Journal of medical genetics | 2006 | PMID: 16443854 |
| HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. | Estep AL | American journal of medical genetics. Part A | 2006 | PMID: 16372351 |
| HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. | Gripp KW | American journal of medical genetics. Part A | 2006 | PMID: 16329078 |
| The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene. | Hoornaert KP | Journal of medical genetics | 2006 | PMID: 16155195 |
| Germline mutations in HRAS proto-oncogene cause Costello syndrome. | Aoki Y | Nature genetics | 2005 | PMID: 16170316 |
| Myopathy with muscle spindle excess: A new congenital neuromuscular syndrome? | Selcen D | Muscle & nerve | 2001 | PMID: 11150980 |
| http://docm.genome.wustl.edu/variants/ENST00000397594:c.34G>A | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HRAS | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/51947641-2e77-498f-93d6-ca73b8e343de | - | - | - | - |
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Text-mined citations for rs104894229 ...
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Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.