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

dbSNP: rs11554290

Total submissions: 12

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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992155	SCV004810324	pathogenic	Noonan syndrome 6	2024-10-07	criteria provided, single submitter	clinical testing
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
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