VCV000012606.31 - ClinVar

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Germline

Top reviewed classifications are shown here.

Submission summary:

36 submissions

18 submitters

26 conditions

Reviewed by expert panel

Pathogenic

Apr 2017 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Variation ID: 12606 Accession: VCV000012606.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 534286 (GRCh38) [ NCBI UCSC ] 11: 534286 (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	Apr 1, 2014	Oct 26, 2024	Apr 3, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.37G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Gly13Cys	missense
NM_176795.5:c.37G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789765.1:p.Gly13Cys	missense
NM_001130442.3:c.37G>T	NP_001123914.1:p.Gly13Cys	missense
NM_001318054.2:c.-283G>T		5 prime UTR
NC_000011.10:g.534286C>A
NC_000011.9:g.534286C>A
NG_007666.1:g.6265G>T
LRG_506:g.6265G>T
LRG_506t1:c.37G>T	LRG_506p1:p.Gly13Cys
	P01112:p.Gly13Cys

... more HGVS ... less HGVS

Protein change

G13C

Other names

p.G13C:GGT>TGT
NM_005343.3(HRAS):c.37G>T

Canonical SPDI

NC_000011.10:534285:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA295247 UniProtKB: P01112#VAR_026107 OMIM: 190020.0007 dbSNP: rs104894228 VarSome

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
Gene	OMIM	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	725
LRRC56		-	-	GRCh38 GRCh38 GRCh37	346	1059

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.
Costello syndrome	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV000013440.46
RASopathy	Pathogenic (2)	criteria provided, single submitter	Sep 24, 2018	RCV000149831.4
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 21, 2022	RCV000207504.10
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000420958.2
Thyroid tumor	Pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000428812.2
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000431688.2
B-cell chronic lymphocytic leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000434069.2
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436007.2
Malignant neoplasm of body of uterus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436205.2
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423190.2
Squamous cell carcinoma of the skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000441514.2
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000424247.2
Pancreatic adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425964.2
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000426653.2
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000417661.2
Acute myeloid leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433893.2
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000439052.2
Neoplasm	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000439954.2
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000444110.2
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445336.2
Neoplasm of uterine cervix	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445225.2
Noonan syndrome	Pathogenic (2)	reviewed by expert panel	Apr 3, 2017	RCV000678903.4
Costello syndrome Epidermal nevus Large congenital melanocytic nevus Linear nevus sebaceous syndrome Malignant tumor of urinary bladder Thyroid cancer, nonmedullary, 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762847.3
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 1, 2018	RCV001813188.4
HRAS-related disorder	Pathogenic (1)	no assertion criteria provided	May 6, 2024	RCV003421918.5
Linear nevus sebaceous syndrome	Likely pathogenic (1)	no assertion criteria provided	Jun 1, 2022	RCV004767004.1
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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 (ClinGen RASopathy ACMG Specifications v1) Method: curation	Noonan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616363.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 16329078‚ 21438134‚ 29493581 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77fd6395-3146-46f0-86ca-08fb626eb660 Comment: The c.37G>T (p.Gly13Cys) 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.37G>T (p.Gly13Cys) 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 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). 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). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys 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). 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): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant tumor of urinary bladder Large congenital melanocytic nevus Epidermal nevus Linear nevus sebaceous syndrome Thyroid cancer, nonmedullary, 2 Costello syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893207.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jun 29, 2010)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062140.5 First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017	Publications: PubMed (3) PubMed: 16329078‚ 17211612‚ 16372351 Comment: The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been … (more) The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been shown to have occurred de novo in at least one individual. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM). (less) Number of individuals with the variant: 5
Pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809475.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Jan 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807270.3 First in ClinVar: Dec 19, 2017 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 25326635
Pathogenic (Jun 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	none provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000263057.1 First in ClinVar: Feb 20, 2016 Last updated: Feb 20, 2016	Publications: PubMed (5) PubMed: 168335863‚ 19213030‚ 21438134‚ 16372351‚ 16329078 Number of individuals with the variant: 1 Age: 10-19 years Sex: female
Pathogenic (Sep 24, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Rasopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917529.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (2) PubMed: 21438134‚ 23429430 Comment: Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four … (more) Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276492 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions and occurs at a codon that is known to be associated with disease (McCormick_2013, Gripp_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060965.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207847.13 First in ClinVar: Feb 20, 2016 Last updated: Mar 04, 2023	Comment: Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., … (more) Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., 2013); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23093928, 16372351, 24803665, 24224811, 16329078, 21438134, 19213030, 28337834, 28973083, 28371260, 16835863, 33240318, 33482860, 29493581) (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003924421.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: PubMed (1) PubMed: 23429430 Comment: A Heterozygous Missense variant c.37G>T in Exon 2 of the HRAS gene that results in the amino acid substitution p.Gly13Cys was identified. The observed variant … (more) A Heterozygous Missense variant c.37G>T in Exon 2 of the HRAS gene that results in the amino acid substitution p.Gly13Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:12606]. The observed variation has been previously reported in patients affected with Costello syndrome (McCormick, Elizabeth M et al., 2013). For these reasons, this variant has been classified as Likely Pathogenic. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Jul 09, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259986.6 First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 16329078‚ 18042262‚ 21438134‚ 16372351‚ 21850009 Comment: For these reasons, this variant has been classified as Pathogenic. This missense change is located in codon 13 of the HRAS gene product. Genetic studies … (more) For these reasons, this variant has been classified as Pathogenic. This missense change is located in codon 13 of the HRAS gene product. Genetic studies of individuals with Costello syndrome show that more than 90% of all HRAS missense variants in these patients occur in either codon 12 or 13 of this gene (PMID: 16329078, 18042262, 21438134, 16372351). This indicates that missense changes involving these two codons are a common cause of disease. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 12606). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16329078, 16372351, 18042262, 21438134). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 13 of the HRAS protein (p.Gly13Cys). (less)
Pathogenic (Apr 01, 2011)	no assertion criteria provided Method: literature only	COSTELLO SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033687.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 01, 2014	Publications: PubMed (3) PubMed: 16835863‚ 19213030‚ 21438134 Comment on evidence: Sol-Church et al. (2006) found that 1 of 42 patients with Costello syndrome (218040) and heterozygous de novo missense mutations involving either glycine-12 or -13 … (more) Sol-Church et al. (2006) found that 1 of 42 patients with Costello syndrome (218040) and heterozygous de novo missense mutations involving either glycine-12 or -13 of the HRAS gene carried a gly13-to-cys (G13C) substitution (37G-A). Piccione et al. (2009) reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome due to the G13C mutation. The characteristic facial features were not apparent until about 4 months of age, when he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. Piccione et al. (2009) noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period. Gripp et al. (2011) examined 12 individuals with Costello syndrome due to the G13C mutation and compared the phenotype to those with the G12S (190020.0003) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia'). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196675.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (2) PubMed: 21495179‚ 21438134 Comment: Variant classified using ACMG guidelines
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: SCV001955013.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Linear nevus sebaceous syndrome Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091323.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
Pathogenic (May 06, 2024)	no assertion criteria provided Method: clinical testing	HRAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117466.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The HRAS c.37G>T variant is predicted to result in the amino acid substitution p.Gly13Cys. This variant was reported in multiple individuals with Costello syndrome and … (more) The HRAS c.37G>T variant is predicted to result in the amino acid substitution p.Gly13Cys. This variant was reported in multiple individuals with Costello syndrome and in at least two individuals it was documented as de novo (see for example - Estep et al. 2006. PubMed ID: 16372351; Table e3, Meng et al. 2017. PubMed ID: 28973083; Table S1, Zhu et al. 2020. PubMed ID: 33240318). Functional studies found this variant impacts HRAS function (Cheng et al. 2012. PubMed ID: 23093928 ). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by ClinGen's RASopathy variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/12606/). Additionally, alternate missense variants (p.Gly13Arg, p.Gly13Asp, p.Gly13Val) have been reported as pathogenic (Sparks et al. 2020. PubMed ID: 33027564; Lefebvre et al. 2021. PubMed ID: 32732226). This variant is interpreted as pathogenic. (less)
Pathogenic (Oct 02, 2014)	no assertion criteria provided Method: literature only	Thyroid tumor (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504407.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (4) PubMed: 17384584‚ 23406027‚ 19773371‚ 19255327 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000311189:c.37G>T
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504408.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000311189:c.37G>T
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: SCV000506577.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506576.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506578.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506579.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	B-cell chronic lymphocytic leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506581.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506580.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506585.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506582.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506583.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506584.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506587.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506586.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506591.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506588.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506589.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
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: SCV000506590.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T
Pathogenic (Aug 24, 2017)	no assertion criteria provided Method: clinical testing	Noonan syndrome Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000805106.1 First in ClinVar: Sep 17, 2018 Last updated: Sep 17, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799200.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
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Comment:

The c.37G>T (p.Gly13Cys) 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 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). 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). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys 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). 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): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong.

Comment:

The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been shown to have occurred de novo in at least one individual. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM).

Comment:

Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276492 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions and occurs at a codon that is known to be associated with disease (McCormick_2013, Gripp_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., 2013); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23093928, 16372351, 24803665, 24224811, 16329078, 21438134, 19213030, 28337834, 28973083, 28371260, 16835863, 33240318, 33482860, 29493581)

Comment:

A Heterozygous Missense variant c.37G>T in Exon 2 of the HRAS gene that results in the amino acid substitution p.Gly13Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:12606]. The observed variation has been previously reported in patients affected with Costello syndrome (McCormick, Elizabeth M et al., 2013). For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This missense change is located in codon 13 of the HRAS gene product. Genetic studies of individuals with Costello syndrome show that more than 90% of all HRAS missense variants in these patients occur in either codon 12 or 13 of this gene (PMID: 16329078, 18042262, 21438134, 16372351). This indicates that missense changes involving these two codons are a common cause of disease. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function. ClinVar contains an entry for this variant (Variation ID: 12606). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16329078, 16372351, 18042262, 21438134). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 13 of the HRAS protein (p.Gly13Cys).

Comment:

The HRAS c.37G>T variant is predicted to result in the amino acid substitution p.Gly13Cys. This variant was reported in multiple individuals with Costello syndrome and in at least two individuals it was documented as de novo (see for example - Estep et al. 2006. PubMed ID: 16372351; Table e3, Meng et al. 2017. PubMed ID: 28973083; Table S1, Zhu et al. 2020. PubMed ID: 33240318). Functional studies found this variant impacts HRAS function (Cheng et al. 2012. PubMed ID: 23093928 ). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by ClinGen's RASopathy variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/12606/). Additionally, alternate missense variants (p.Gly13Arg, p.Gly13Asp, p.Gly13Val) have been reported as pathogenic (Sparks et al. 2020. PubMed ID: 33027564; Lefebvre et al. 2021. PubMed ID: 32732226). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Assessing genotype-phenotype correlation in Costello syndrome using a severity score.	McCormick EM	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 23429430
Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.	Ho AL	The New England journal of medicine	2013	PMID: 23406027
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
Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review.	Axelrad ME	American journal of medical genetics. Part C, Seminars in medical genetics	2011	PMID: 21495179
Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.	Gripp KW	American journal of medical genetics. Part A	2011	PMID: 21438134
Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma.	Hoftijzer H	European journal of endocrinology	2009	PMID: 19773371
Phase II trial of sorafenib in metastatic thyroid cancer.	Kloos RT	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19255327
A premature infant with Costello syndrome due to a rare G13C HRAS mutation.	Piccione M	American journal of medical genetics. Part A	2009	PMID: 19213030
Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.	Schulz AL	Clinical genetics	2008	PMID: 18042262
Hyperactive Ras in developmental disorders and cancer.	Schubbert S	Nature reviews. Cancer	2007	PMID: 17384584
An unexpected new role of mutant Ras: perturbation of human embryonic development.	Kratz CP	Journal of molecular medicine (Berlin, Germany)	2007	PMID: 17211612
Paternal bias in parental origin of HRAS mutations in Costello syndrome.	Sol-Church K	Human mutation	2006	PMID: 16835863
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
-	-	-	-	PMID: 168335863
http://docm.genome.wustl.edu/variants/ENST00000311189:c.37G>T	-	-	-	-
http://docm.genome.wustl.edu/variants/ENST00000397594:c.37G>T	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77fd6395-3146-46f0-86ca-08fb626eb660	-	-	-	-
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Text-mined citations for rs104894228 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894228 ...