ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.3076C>T (p.Pro1026Ser) (rs201874067)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681418 SCV000808881 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing The P1026S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P1026S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P1026S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001058885 SCV001223483 uncertain significance Noonan syndrome 9 2020-02-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1026 of the SOS2 protein (p.Pro1026Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs201874067, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 561959). 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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