ClinVar Miner

Submissions for variant NM_006939.4(SOS2):c.800T>C (p.Met267Thr) (rs797045167)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414175 SCV000491679 pathogenic not provided 2017-11-17 criteria provided, single submitter clinical testing The M267T variant in the SOS2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a different missense variant in the same residue, M267K, was identified as a de novo change in a patient with Noonan syndrome (Yamamoto et al., 2015). A second missense variant in the same residue, M267R, was identified in two individuals with Noonan syndrome, and functional studies of M267R indicate that it promotes enhanced phosphorylation of ERK (Cordeddu et al., 2015). The M267T 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 M267T 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret M267T as a pathogenic variant
Department of Human Genetics, University Hospital Magdeburg RCV001250768 SCV001426181 pathogenic Noonan syndrome 9 2020-07-02 criteria provided, single submitter clinical testing This variant has been previously reported as pathogenic (PS1). It is absent from gnomAD (PM2). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.868 (PP3) and the variant has been classified as pathogenic in ClinVar (PP5).

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