Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV001663837 | SCV001879577 | pathogenic | not provided | 2021-02-03 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. 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 mutations 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 |
RCV001663837 | SCV005733977 | uncertain significance | not provided | 2024-06-02 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 617 of the NOTCH3 protein (p.Cys617Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NOTCH3-related condition (Invitae). ClinVar contains an entry for this variant (Variation ID: 1256495). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys617 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 30402942), which suggests that this may be a clinically significant amino acid residue. 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. |