Submissions for variant NM_002524.5(NRAS):c.35G>T (p.Gly12Val)

dbSNP: rs121913237

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037576	SCV000061234	pathogenic	Noonan syndrome	2010-08-06	criteria provided, single submitter	clinical testing	The Gly12Val variant has not been reported in the literature as a germline varia nt and has not been identified in our laboratory. However, it has been reported as a somatic mutation in several types of cancer, including leukemia and melanom a (COSMIC, Houben 2004, Tartaglia, 2004).
GeneDx	RCV000158986	SCV000208925	pathogenic	not provided	2019-11-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging gain-of-function effect due to promotion of a shift towards the constitutively activated GTP-bound conformation of the protein, and enhanced ERK and AKT activation basally (Altmller 2017); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20736745, 25691160, 15831708, 20619739, 17699718, 28594414, 18952898, 15046639, 14982869, 26619011, 21829508, 21729679, 21305640, 16273091, 22589270)
Invitae	RCV001377735	SCV001575141	likely pathogenic	RASopathy	2020-08-06	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28098151, 28594414). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 NRAS protein function. This variant has been observed in individual(s) with clinical features of a RASopathy condition (PMID: 28594414). ClinVar contains an entry for this variant (Variation ID: 40470). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 12 of the NRAS protein (p.Gly12Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. Experimental studies have shown that this variant affects NRAS protein function (PMID: 21263000).
Database of Curated Mutations (DoCM)	RCV000439421	SCV000503701	pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419124	SCV000503702	pathogenic	Melanoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429393	SCV000503703	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438750	SCV000503704	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421072	SCV000503705	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432178	SCV000503706	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438967	SCV000503707	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423890	SCV000503708	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000158986	SCV002035696	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000158986	SCV002037405	pathogenic	not provided		no assertion criteria provided	clinical testing