ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)

dbSNP: rs11554290
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Total submissions: 29
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037574 SCV000061232 pathogenic Non-small cell lung carcinoma 2011-08-12 criteria provided, single submitter clinical testing
GeneDx RCV000413804 SCV000490986 pathogenic not provided 2023-09-18 criteria provided, single submitter clinical testing Published functional studies demonstrate increased levels of Nras-GTP (Kong et al., 2016) and constitutive activation of the MAPK pathway (Demin et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 6587382, 14508525, 19880792, 25142146, 22773810, 1654209, 29883661, 18633438, 23392294, 24006476, 20526288, 24077912, 27109513, 31228933, 23855428, 22237106, 17910045)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV000413804 SCV002525697 pathogenic not provided 2021-09-03 criteria provided, single submitter clinical testing This is a recurrent pathogenic variant that has been reported previously in multiple individuals with kaposiform lymphangiomatosis (KLA), as well as an individual with a generalized lymphatic anomaly (GLA), also known as diffuse lymphangiomatosis (PMID: 30542204, PMID: 31511039, PMID: 29397482). This change is also reported as an oncogenic variant found in multiple tumor types, especially melanoma (COSMIC and cBioPortal Databases). This variant is not present in large population cohorts (Genome Aggregation Database v2.1.1). The p.Gln61Arg variant leads to constitutive activation of the NRAS protein (PMID: 30542204, PMID: 29397482).
Clinical Genomics Laboratory, Washington University in St. Louis RCV000114744 SCV004176931 pathogenic Large congenital melanocytic nevus 2023-10-14 criteria provided, single submitter clinical testing The NRAS c.182A>G (p.Gln61Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with melanocytic nevus (Kinsler VA et al., PMID: 23392294; Abdulmajid L et al., PMID: 34255877; Francis JH et al., PMID: 29332123; Colebatch AJ et al., PMID: 30772300; Tschandl P et al., PMID: 23861977; Dessars B et al., PMID: 18633438). This variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar ID: 13900) and in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV54736340). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. The same amino acid change (p.Gln61Arg), resulting from a different nucleotide change, c.182_183delinsGG, has been reported in melanoma and is considered pathogenic (Ball NJ et al., PMID: 8120410; ClinVar ID: 375873). The NRAS c.182A>G (p.Gln61Arg) variant resides within a GTP-binding site of NRAS that is defined as a critical function domain (Scheffzek K et al., PMID: 9219684). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on NRAS function. In support of this prediction, functional studies show that this variant impairs the GTPase activity and activates Ras/Raf/MEK/MAPK pathway, leading to cellular transformation (Ross AL et al., PMID: 21754924; Ruan Y et al., PMID: 25395461). The NRAS gene is defined by the ClinGen's RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the NRAS c.182A>G (p.Gln61Arg) variant is classified as pathogenic.
OMIM RCV000014914 SCV000035170 pathogenic Thyroid cancer, nonmedullary, 2 2014-01-15 no assertion criteria provided literature only
OMIM RCV000032847 SCV000056616 pathogenic Epidermal nevus 2014-01-15 no assertion criteria provided literature only
OMIM RCV000114744 SCV000148627 pathogenic Large congenital melanocytic nevus 2014-01-15 no assertion criteria provided literature only
OMIM RCV000114745 SCV000148628 pathogenic Neurocutaneous melanocytosis 2014-01-15 no assertion criteria provided literature only
OMIM RCV000148032 SCV000195534 pathogenic Linear nevus sebaceous syndrome 2014-01-15 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424960 SCV000503611 pathogenic Melanoma 2016-03-10 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435687 SCV000503612 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000037574 SCV000503613 pathogenic Non-small cell lung carcinoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424721 SCV000503614 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438052 SCV000503615 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420832 SCV000503616 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430593 SCV000503617 likely pathogenic Nasopharyngeal neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441317 SCV000503618 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419710 SCV000503619 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430407 SCV000503620 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440367 SCV000503621 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422278 SCV000503622 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432961 SCV000503623 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439264 SCV000503624 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422078 SCV000503625 likely pathogenic Adrenal cortex carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431883 SCV000503626 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445249 SCV000503627 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424455 SCV000503628 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000413804 SCV001979371 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000413804 SCV001980093 pathogenic not provided no assertion criteria provided clinical testing

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