ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.2443A>G (p.Asn815Asp) (rs886041958)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000276484 SCV000330768 uncertain significance not provided 2016-09-09 criteria provided, single submitter clinical testing The N815D variant in the SOS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The N815D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N815D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N815D as a variant of uncertain significance
Invitae RCV000703487 SCV000832390 uncertain significance Noonan syndrome 9 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 815 of the SOS2 protein (p.Asn815Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SOS2-related disease. ClinVar contains an entry for this variant (Variation ID: 280818). 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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