ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.1273A>G (p.Lys425Glu)

gnomAD frequency: 0.00001  dbSNP: rs372203654
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000331734 SCV000330689 uncertain significance not provided 2016-07-29 criteria provided, single submitter clinical testing The K425Evariant in the SOS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K425E variant was not observed at any significant frequency in approximately 6,500 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 K425E 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. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K425E as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001859539 SCV002194278 uncertain significance Noonan syndrome 9 2023-05-05 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 425 of the SOS2 protein (p.Lys425Glu). 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 SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 280746). This variant has not been reported in the literature in individuals affected with SOS2-related conditions.
Genome-Nilou Lab RCV001859539 SCV002763087 uncertain significance Noonan syndrome 9 criteria provided, single submitter clinical testing

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