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 2019-07-08 criteria provided, single submitter clinical testing The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data.
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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