ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.1973A>G (p.Lys658Arg)

gnomAD frequency: 0.00001  dbSNP: rs1317956888
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002254851 SCV002525992 uncertain significance Noonan syndrome 9 2022-01-27 criteria provided, single submitter clinical testing The SOS2 c.1973A>G (p.Lys658Arg) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/14-50623801-T-C ). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the RASopathy Variant Curation Expert Panel (PMID:29493581): PM2, PP2, BP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV002254851 SCV003289449 uncertain significance Noonan syndrome 9 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 658 of the SOS2 protein (p.Lys658Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1691522). 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 not expected to disrupt SOS2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV004047395 SCV005025045 uncertain significance Cardiovascular phenotype 2023-11-09 criteria provided, single submitter clinical testing The p.K658R variant (also known as c.1973A>G), located in coding exon 12 of the SOS2 gene, results from an A to G substitution at nucleotide position 1973. The lysine at codon 658 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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