ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.3584C>T (p.Ala1195Val) (rs753151750)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486673 SCV000570367 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing The A1195V variant in the SOS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A1195V variant is observed in 1/16,234 (0.006%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The A1195V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A1195V as a variant of uncertain significance.
Invitae RCV000652813 SCV000774685 uncertain significance Noonan syndrome 9 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1195 of the SOS2 protein (p.Ala1195Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs753151750, ExAC 0.006%). This variant has not been reported in the literature in individuals with SOS2-related disease. ClinVar contains an entry for this variant (Variation ID: 421233). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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