ClinVar Genomic variation as it relates to human health
NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)
Variation ID: 12597 Accession: VCV000012597.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 25227346 (GRCh38) [ NCBI UCSC ] 12: 25380280 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 8, 2016 Feb 14, 2024 Nov 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004985.5:c.178G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004976.2:p.Gly60Ser missense NM_033360.4:c.178G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Gly60Ser missense NM_001369786.1:c.178G>A NP_001356715.1:p.Gly60Ser missense NM_001369787.1:c.178G>A NP_001356716.1:p.Gly60Ser missense NC_000012.12:g.25227346C>T NC_000012.11:g.25380280C>T NG_007524.2:g.28658G>A LRG_344:g.28658G>A LRG_344t1:c.178G>A LRG_344p1:p.Gly60Ser LRG_344t2:c.178G>A LRG_344p2:p.Gly60Ser P01116:p.Gly60Ser - Protein change
- G60S
- Other names
- p.G60S:GGT>AGT
- Canonical SPDI
- NC_000012.12:25227345:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KRAS | No evidence available | No evidence available |
GRCh38 GRCh37 |
455 | 512 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Mar 25, 2022 | RCV000013428.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 25, 2022 | RCV000157934.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 12, 2022 | RCV000689097.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2019 | RCV002470709.1 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Mar 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 3
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002318974.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.178G>A;p.(Gly60Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12597; PMID: 19396835) -PS4. The … (more)
The c.178G>A;p.(Gly60Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12597; PMID: 19396835) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RAS) - PM1. This variant is not present in population databases (rs104894359- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 12586) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19396835) - PM6. Missense variant in KRAS that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Aug 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768383.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
A heterozygous missense variant, NM_004985.4(KRAS):c.178G>A, has been identified in exon 3 of 5 of the KRAS gene. The variant is predicted to result in a … (more)
A heterozygous missense variant, NM_004985.4(KRAS):c.178G>A, has been identified in exon 3 of 5 of the KRAS gene. The variant is predicted to result in a minor amino acid change from glycine to serine at position 60 of the protein (NP_004976.2(KRAS):p.(Gly60Ser)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC) and is known as a mutational hotspot for Noonan syndrom and related disorders that locates within the critical binding and interaction site of Ras domain (Gremer, L. et al. (2011)). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). The variant has been previously described as a known pathogenic variant in multiple patients with Noonan syndrome (ClinVar, Kratz, CP. et al. (2009), Leung, GKC. et al. (2018), Chen, H. et al. (2019)). Multiple variants in the same codon resulting in various changes have also been reported as pathogenic (ClinVar, Zenker, M. et al. (2007), Nosan, G. et al. (2013), Chen, H. et al. (2019)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
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Pathogenic
(Nov 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000207869.15
First in ClinVar: Feb 24, 2015 Last updated: May 06, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 28639239, 19396835, 30732632, 31219622, 35441720) (less)
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Pathogenic
(Jul 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000816735.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, … (more)
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly60 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474404, 26242988, 28650561). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KRAS protein function. ClinVar contains an entry for this variant (Variation ID: 12597). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19396835, 30732632). 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 serine, which is neutral and polar, at codon 60 of the KRAS protein (p.Gly60Ser). (less)
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Pathogenic
(May 01, 2009)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033675.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 17, 2021 |
Comment on evidence:
In a patient with Noonan syndrome-3 (NS3; 609942) and craniosynostosis, Kratz et al. (2009) identified a de novo heterozygous 178G-A transition in the KRAS gene, … (more)
In a patient with Noonan syndrome-3 (NS3; 609942) and craniosynostosis, Kratz et al. (2009) identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. A mutation in this same codon (G60R; 190070.0009) has been found in a patient with cardiofaciocutaneous syndrome (CFC2; 615278). (less)
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Pathogenic
(Jul 05, 2021)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome 3
Affected status: yes
Allele origin:
de novo
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Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong
Accession: SCV002498739.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
This variant c.178G>A(p.G60S) was previously reported to be de novo in a patient with Noonan syndrome [PMID:19396835] (PS2). The p.Gly60 amino acid residue in KRAS … (more)
This variant c.178G>A(p.G60S) was previously reported to be de novo in a patient with Noonan syndrome [PMID:19396835] (PS2). The p.Gly60 amino acid residue in KRAS has been determined to be clinically significant and confirmed by functional studies [PMID: 16474404, 20949621, 26242988, 28650561] (PM1). The variant is absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3) .This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 12597] (PP5). This variant c.178G>A(p.G60S) is interpreted as pathogenic according to ACMG/AMP guidelines. (less)
Clinical Features:
Increased nuchal translucency (present) , Overgrowth (present) , Abnormal morphology of the great vessels (present)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. | Chen H | Orphanet journal of rare diseases | 2019 | PMID: 30732632 |
Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. | Ueda K | American journal of medical genetics. Part A | 2017 | PMID: 28650561 |
The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. | Joyce S | European journal of human genetics : EJHG | 2016 | PMID: 26242988 |
Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. | Kratz CP | American journal of medical genetics. Part A | 2009 | PMID: 19396835 |
Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. | Niihori T | Nature genetics | 2006 | PMID: 16474404 |
- | - | - | - | DOI: 10.1002/pd.6151 |
- | - | - | - | DOI: doi/10.1002/pd.6151 |
Text-mined citations for rs104894359 ...
HelpRecord last updated Feb 14, 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.