Submissions for variant NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)

gnomAD frequency: 0.00001  dbSNP: rs112445441

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038269	SCV000061938	pathogenic	Non-small cell lung carcinoma	2011-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092389	SCV001248878	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266168	SCV001444340	pathogenic	Inborn genetic diseases	2018-07-19	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526657	SCV001737088	pathogenic	Nevus sebaceous		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001092389	SCV002016398	pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813183	SCV002060774	pathogenic	Noonan syndrome and Noonan-related syndrome	2023-02-11	criteria provided, single submitter	clinical testing	This missense variant results in a change from glycine to aspartic acid at amino acid position 13. It has been previously reported in a somatic mosaic state in individuals with myelodysplastic/myeloproliferative disease (PMID: 22571758). It was also identified in a patient with Oculoectodermal syndrome (PMID: 25808193) and found in a case of RAS-associated autoimmune leukoproliferative disorder (PMID: 32441320). This variant is in the P-loop and mutational hotspot defined by ClinGen expert panel. Additionally the same amino acid change, p.Gly13Asp, in the HRAS gene has been reported as pathogenic in several patients (SickKids, internal data). This variant is observed at an allele frequency of 0.00031% in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as pathogenic (PS1, PS4_m, PM1, PM2, PP3, PP5).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857340	SCV002117438	pathogenic	RASopathy	2024-03-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813034	SCV005438357	pathogenic	Familial pancreatic carcinoma	2024-12-18	criteria provided, single submitter	clinical testing
OMIM	RCV000013409	SCV000033656	pathogenic	Breast adenocarcinoma	2015-07-01	no assertion criteria provided	literature only
OMIM	RCV000144967	SCV000191994	pathogenic	Juvenile myelomonocytic leukemia	2015-07-01	no assertion criteria provided	literature only
OMIM	RCV000144968	SCV000191995	pathogenic	Autoimmune lymphoproliferative syndrome type 4	2015-07-01	no assertion criteria provided	literature only
OMIM	RCV000791297	SCV000930607	pathogenic	OCULOECTODERMAL SYNDROME, SOMATIC	2015-07-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001092389	SCV001552665	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092389	SCV001952799	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001092389	SCV001972639	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001839444	SCV002099548	not provided	Encephalocraniocutaneous lipomatosis		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004549358	SCV004742495	pathogenic	KRAS-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.