Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000521629 | SCV000620703 | pathogenic | not provided | 2017-09-27 | criteria provided, single submitter | clinical testing | The C108F variant in the NOTCH3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The C108F variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C108F 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 2 domain, a position that is conserved across species. Other missense variants at this residue (C108S, C108R, C108Y, C108W) have been reported in the Human Gene Mutation Database in association with CADASIL (Stenson et al., 2014), supporting the functional importance of this region of the protein.In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C108F as a pathogenic variant. |
| Athena Diagnostics | RCV000521629 | SCV001143376 | pathogenic | not provided | 2023-03-09 | criteria provided, single submitter | clinical testing | This variant has been identified in at least one individual with clinical features associated with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673). |