ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1276C>A (p.Gln426Lys)

dbSNP: rs1558474706
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680953 SCV000808402 likely pathogenic not provided 2018-02-19 criteria provided, single submitter clinical testing The Q426K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016). Q426K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located within the Pleckstrin homology domain, which is critical for protein function (Tartaglia et al., 2010; Lepri et al., 2011). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp RCV000800990 SCV000940738 uncertain significance RASopathy 2022-03-19 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 561622). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 426 of the SOS1 protein (p.Gln426Lys).

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