Submissions for variant NM_005633.4(SOS1):c.350T>G (p.Val117Gly)

gnomAD frequency: 0.00001  dbSNP: rs201085754

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000520887	SCV000616433	likely benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The c.350T>G (p.Val117Gly) variant has been identified in a patient with clinical features of a RASopathy with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; GeneDx, Partners LMM; GTR ID's: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). Computational prediction tools and conservation analysis suggest that the p.Val117Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, BS2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038552	SCV000062230	uncertain significance	not specified	2014-09-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val117Gly varia nt in SOS1 has been identified in 1 stillborn fetus and 1 Ashkenazi Jewish indiv idual with Noonan syndrome who also carried a pathogenic variant in PTPN11. In addition, the variant was also identified in the unaffected mothers of both of t hese individuals (LMM unpublished data, pers. com. Cedars-Sinai). This variant h as also been identified in 0.1% (1/943) of European chromosomes by the ClinSeq p roject (dbSNP rs201085754). Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Val117Gly variant is uncertain, its presence in 3 apparently healthy individuals suggest that it is more likely to be benign.
GeneDx	RCV000038552	SCV000209093	likely benign	not specified	2016-07-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520887	SCV000834528	likely benign	RASopathy	2025-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453317	SCV002613697	uncertain significance	Cardiovascular phenotype	2025-02-21	criteria provided, single submitter	clinical testing	The p.V117G variant (also known as c.350T>G), located in coding exon 4 of the SOS1 gene, results from a T to G substitution at nucleotide position 350. The valine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038552	SCV004099710	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.350T>G (p.Val117Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.350T>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The available evidence is currently insufficient to determine the role of this variant in disease. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.