ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.622G>T (p.Ala208Ser) (rs61755579)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000652814 SCV000774686 uncertain significance Noonan syndrome 9 2020-09-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 208 of the SOS2 protein (p.Ala208Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs61755579, ExAC 0.03%). This variant has not been reported in the literature in individuals with a SOS2-related disease. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175494 SCV001339087 uncertain significance not specified 2020-10-01 criteria provided, single submitter clinical testing Variant summary: SOS2 c.622G>T (p.Ala208Ser) results in a conservative amino acid change located in the Dbl homology (DH) domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 245786 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.622G>T has been reported in the literature in individuals affected with pediatric heart disease (Reuter_2020). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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