1-114709651-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_SupportingPP3
This summary comes from the ClinGen Evidence Repository: The NM_002524.5:c.368G>A variant in NRAS is a missense variant predicted to cause substitution of arginine by lysine at amino acid 123 (p.Arg123Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.759, which is above the threshold of 0.7, evidence that correlates with impact to NRAS function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_Supporting, PP3. (ClinGen RASopathy VCEP specifications version 2.1; 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA177518/MONDO:0021060/039
Frequency
Consequence
NM_002524.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461476Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727074
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 22, 2013 | 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. - |
Noonan syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 07, 2024 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2022 | 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 - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 15, 2022 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at