ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.350T>G (p.Val117Gly) (rs201085754)

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Total submissions: 4
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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,Partners HealthCare 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 In addition, the variant was also identified in the unaffected mothers of both of t hese individuals (LMM unpublished data, pers.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.
Invitae RCV000520887 SCV000834528 uncertain significance Rasopathy 2018-02-19 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 117 of the SOS1 protein (p.Val117Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs201085754, ExAC 0.005%). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 45364). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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