Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19661383, 22306671, 17517660, 25705018, 25691160, 21063026, 34056834, 22571758, 29493581, 21079152, 17875937, 27577878, 35116442)
ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.37G>T (p.Gly13Cys)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004985.5(KRAS):c.37G>T (p.Gly13Cys)
Variation ID: 45123 Accession: VCV000045123.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 25245348 (GRCh38) [ NCBI UCSC ] 12: 25398282 (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 31, 2015 Oct 21, 2023 Jan 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004985.5:c.37G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004976.2:p.Gly13Cys missense NM_033360.4:c.37G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Gly13Cys missense NM_001369786.1:c.37G>T NP_001356715.1:p.Gly13Cys missense NM_001369787.1:c.37G>T NP_001356716.1:p.Gly13Cys missense NM_033360.3:c.37G>T NC_000012.12:g.25245348C>A NC_000012.11:g.25398282C>A NG_007524.2:g.10656G>T LRG_344:g.10656G>T LRG_344t1:c.37G>T LRG_344p1:p.Gly13Cys LRG_344t2:c.37G>T LRG_344p2:p.Gly13Cys - Protein change
- G13C
- Other names
- -
- Canonical SPDI
- NC_000012.12:25245347: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| KRAS | No evidence available | No evidence available |
GRCh38 GRCh37 |
463 | 521 | |
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 (2) |
criteria provided, single submitter
|
Sep 17, 2012 | RCV000038268.6 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2023 | RCV000144972.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000443868.1 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 21, 2022 | RCV000681039.7 | |
|
KRAS-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003335071.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000808492.3
First in ClinVar: Sep 22, 2018 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19661383, 22306671, 17517660, 25705018, 25691160, 21063026, 34056834, 22571758, 29493581, 21079152, 17875937, 27577878, 35116442) (less)
|
|
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Pathogenic
(Jan 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000928185.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019
Comment:
Patient analyzed with Primary Immunodeficiency Panel
|
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|
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Pathogenic
(Sep 17, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
Non-small cell lung carcinoma
Affected status: not provided
Allele origin:
somatic
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061937.4
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 22
|
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Likely pathogenic
(Jan 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autoimmune lymphoproliferative syndrome type 4
Affected status: yes
Allele origin:
germline
|
Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine
Accession: SCV003837570.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autoimmune lymphoproliferative syndrome type 4
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013692.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29493581. Predicted Consequence/Location:). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045123 / PMID: 27577878). Different missense changes at the same codon (p.Gly13Ala, p.Gly13Arg, p.Gly13Asp, p.Gly13Ser, p.Gly13Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012580, VCV000012593, VCV000045124, VCV000375967, VCV000375968, VCV001691382 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Thrombocytopenia (present) , Recurrent fever (present) , Cellulitis (present) , Recurrent otitis media (present) , Generalized lymphadenopathy (present)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
KRAS-related disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046132.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a … (more)
This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a plasmid-encoding mutant G13C showed an increased amount of active RAS versus wild-type KRAS suggesting a gain-of-function effect (PMID: 21079152). The c.37G>T (p.Gly13Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.37G>T (p.Gly13Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.37G>T (p.Gly13Cys) variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 10, 2011)
|
no assertion criteria provided
Method: literature only
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RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000191999.2
First in ClinVar: Nov 22, 2014 Last updated: Sep 08, 2016 |
Comment on evidence:
In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous c.37G-T transversion in … (more)
In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function. (less)
|
|
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Pathogenic
(Jul 14, 2015)
|
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: SCV000504463.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Non-small cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504464.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552227.2 First in ClinVar: Apr 13, 2021 Last updated: Nov 29, 2022 |
Number of individuals with the variant: 3
|
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29493581. Predicted Consequence/Location:). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045123 / PMID: 27577878). Different missense changes at the same codon (p.Gly13Ala, p.Gly13Arg, p.Gly13Asp, p.Gly13Ser, p.Gly13Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012580, VCV000012593, VCV000045124, VCV000375967, VCV000375968, VCV001691382 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a plasmid-encoding mutant G13C showed an increased amount of active RAS versus wild-type KRAS suggesting a gain-of-function effect (PMID: 21079152). The c.37G>T (p.Gly13Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.37G>T (p.Gly13Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.37G>T (p.Gly13Cys) variant is classified 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:
Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19661383, 22306671, 17517660, 25705018, 25691160, 21063026, 34056834, 22571758, 29493581, 21079152, 17875937, 27577878, 35116442)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29493581. Predicted Consequence/Location:). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045123 / PMID: 27577878). Different missense changes at the same codon (p.Gly13Ala, p.Gly13Arg, p.Gly13Asp, p.Gly13Ser, p.Gly13Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012580, VCV000012593, VCV000045124, VCV000375967, VCV000375968, VCV001691382 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a plasmid-encoding mutant G13C showed an increased amount of active RAS versus wild-type KRAS suggesting a gain-of-function effect (PMID: 21079152). The c.37G>T (p.Gly13Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.37G>T (p.Gly13Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.37G>T (p.Gly13Cys) variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| 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 |
| Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. | Bokemeyer C | Annals of oncology : official journal of the European Society for Medical Oncology | 2011 | PMID: 21228335 |
| Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. | Niemela JE | Blood | 2011 | PMID: 21079152 |
| Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. | Douillard JY | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 20921465 |
| Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. | Peeters M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 20921462 |
| Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. | Neumann J | Pathology, research and practice | 2009 | PMID: 19679400 |
| Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. | Bokemeyer C | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19114683 |
| Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. | Riely GJ | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18794081 |
| Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. | Amado RG | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18316791 |
| KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. | Lièvre A | Cancer research | 2006 | PMID: 16618717 |
| Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. | Rothenberg ML | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16361624 |
| KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. | Pao W | PLoS medicine | 2005 | PMID: 15696205 |
| BRAF and RAS mutations in human lung cancer and melanoma. | Brose MS | Cancer research | 2002 | PMID: 12460918 |
| http://docm.genome.wustl.edu/variants/ENST00000256078:c.37G>T | - | - | - | - |
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Text-mined citations for rs121913535 ...
HelpThese 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 May 27, 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.