Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV001288892 | SCV001476291 | pathogenic | not provided | 2023-11-07 | criteria provided, single submitter | clinical testing | This variant has been identified in at least one individual with clinical features associated with this gene. 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. Computational tools predict that this variant is damaging. 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). |
| Labcorp Genetics |
RCV001288892 | SCV002278171 | uncertain significance | not provided | 2020-12-20 | criteria provided, single submitter | clinical testing | 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 NOTCH3 protein function. This variant has not been reported in the literature in individuals with NOTCH3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 1022 of the NOTCH3 protein (p.Cys1022Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. |