Submissions for variant NM_002524.5(NRAS):c.368G>A (p.Arg123Lys)

dbSNP: rs727503347

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151575	SCV000199725	uncertain significance	not specified	2013-08-22	criteria provided, single submitter	clinical testing	The Arg123Lys variant in NRAS has not been previously identified in individuals with clinical features of a Noonan spectrum disorder, or in large population stu dies. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. Additional information is needed to fully assess the clini cal significance of this variant.
GeneDx	RCV001823120	SCV002072845	uncertain significance	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850066	SCV002302727	uncertain significance	RASopathy	2022-07-15	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with NRAS-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. ClinVar contains an entry for this variant (Variation ID: 164809). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 123 of the NRAS protein (p.Arg123Lys).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055078	SCV005689181	uncertain significance	Noonan syndrome 6	2024-08-07	criteria provided, single submitter	clinical testing	The NRAS c.368G>A (p.Arg123Lys) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge, this prediction has not been confirmed by functional studies. This variant has been reported in one individual with Costello syndrome who, in addition, had a mutation in HRAS (PMID: 25133308). To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.