ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.179G>T (p.Gly60Val)
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_004985.5(KRAS):c.179G>T (p.Gly60Val)
Variation ID: 163766 Accession: VCV000163766.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 25227345 (GRCh38) [ NCBI UCSC ] 12: 25380279 (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 Feb 2, 2015 Feb 14, 2024 Jul 26, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004985.5:c.179G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004976.2:p.Gly60Val missense NM_033360.4:c.179G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Gly60Val missense NM_001369786.1:c.179G>T NP_001356715.1:p.Gly60Val missense NM_001369787.1:c.179G>T NP_001356716.1:p.Gly60Val missense NC_000012.12:g.25227345C>A NC_000012.11:g.25380279C>A NG_007524.2:g.28659G>T LRG_344:g.28659G>T LRG_344t1:c.179G>T LRG_344p1:p.Gly60Val LRG_344t2:c.179G>T LRG_344p2:p.Gly60Val - Protein change
- G60V
- Other names
- p.G60V:GGT>GTT
- Canonical SPDI
- NC_000012.12:25227344:C:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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
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
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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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Likely pathogenic (1) |
no assertion criteria provided
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Jul 19, 2013 | RCV000150889.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jul 19, 2013 | RCV000157936.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2021 | RCV000212500.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2022 | RCV001850055.3 |
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
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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
(Nov 07, 2017)
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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: SCV000207871.11
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
The G60V variant has been reported as an apparently de novo variant in an infant who exhibited a severe phenotype and expired due to hypertrophic … (more)
The G60V variant has been reported as an apparently de novo variant in an infant who exhibited a severe phenotype and expired due to hypertrophic cardiomyopathy (Nosan et al., 2013). It has also been observed at GeneDx to occur apparently de novo in an affected patient. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). G60V occurs at a highly conserved position within the Switch II domain (Schubbert et al., 2007). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G60S/R) and in a nearby residue (T58I) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. (less)
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Likely pathogenic
(Oct 26, 2021)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502780.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jul 26, 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: SCV002228921.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 163766). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 24382853). In at … (more)
ClinVar contains an entry for this variant (Variation ID: 163766). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 24382853). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs727503108, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the KRAS protein (p.Gly60Val). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 19396835, 30732632). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jul 19, 2013)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Cardio-facio-cutaneous syndrome (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198469.4
First in ClinVar: Feb 02, 2015 Last updated: May 29, 2016 |
Comment:
The Gly60Val variant in KRAS has not been previously identified in our laborator y, nor has this specific variant been reported in the literature in … (more)
The Gly60Val variant in KRAS has not been previously identified in our laborator y, nor has this specific variant been reported in the literature in individuals with clinical features of Noonan spectrum disorders. However, two different amin o acid changes at the same codon, Gly60Arg and Gly60Ser, have been reported in t wo individuals with Cardio-facio-cutaneous syndrome and Noonan syndrome, respect ively (CFC; Niihori 2006, Kratz 2009). Parental testing confirmed the Gly60Ser h ad occured de novo in that patient (Kratz 2009). This variant has been observed to occur as a somatic change in two metastatic colorectal cancer tissues and ot her variants at this codon have been identified as somatic changes in other tiss ue types (Okayama 2011, Guedes 2013, COSMIC database). Functional studies sugges t the Gly60 is an important residue since it interacts with ?-phosphate of GTP a nd is a conserved amino acid across the superfamily of GTPases (Guedes 2013). Fu rthermore, this variant was absent in large, ethnically-distinct populations. Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that the Gly60Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, though additional studies are requi red to fully establish its clinical significance. (less)
Number of individuals with the variant: 2
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Likely pathogenic
(Jul 19, 2013)
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no assertion criteria provided
Method: clinical testing
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Non-small cell lung carcinoma
(Somatic mutation)
Affected status: not provided
Allele origin:
somatic
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198468.2
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Number of individuals with the variant: 2
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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 |
A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study. | Nosan G | Croatian medical journal | 2013 | PMID: 24382853 |
High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer. | Guedes JG | BMC cancer | 2013 | PMID: 23548132 |
The importance of evaluation of DNA amplificability in KRAS mutation testing with dideoxy sequencing using formalin-fixed and paraffin-embedded colorectal cancer tissues. | Okayama N | Japanese journal of clinical oncology | 2011 | PMID: 20926413 |
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 |
Text-mined citations for rs727503108 ...
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.