ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.35G>T (p.Gly12Val) (rs121913237)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 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. This variant is not present in population databases (ExAC no frequency). 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). 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 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. Experimental studies have shown that this variant affects NRAS protein function (PMID: 21263000). 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.
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 Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
PerkinElmer Genomics RCV001781336 SCV002018372 pathogenic Noonan syndrome 6 2020-06-18 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000158986 SCV002035696 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000158986 SCV002037405 pathogenic not provided no assertion criteria provided clinical testing

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