ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.665G>A (p.Cys222Tyr) (rs1555729452)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517527 SCV000614327 pathogenic not provided 2015-08-15 criteria provided, single submitter clinical testing
GeneDx RCV000517527 SCV000617299 likely pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing The C222Y variant in the NOTCH3 gene has been reported in association with CADASIL (Kalimo et al., 2002; Federico et al., 2005). Different missense variants of the same amino acid (C222G, C222S, C222R) have also been reported in patients with CADASIL (Joutel et al., 1997; Stenson et al., 2014), highlighting the importance of this amino acid in the protein. The C222Y 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 Cysteine residue within the EGF-like 5 domain, a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The C222Y variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret C222Y as a likely pathogenic variant.

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