Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485488 | SCV000568237 | likely pathogenic | not provided | 2022-07-19 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24844136, 22639698, 31443546) |
| Athena Diagnostics | RCV000485488 | SCV000614278 | pathogenic | not provided | 2023-10-02 | 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. Computational tools predict that this variant is damaging. 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). |
| Labcorp Genetics |
RCV000485488 | SCV002280861 | likely pathogenic | not provided | 2022-11-25 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 419978). This missense change has been observed in individuals with clinical features of CADASIL (PMID: 22639698, 31443546; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1061 of the NOTCH3 protein (p.Cys1061Tyr). This variant disrupts the p.Cys1061 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 33942994), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Mayo Clinic Laboratories, |
RCV000485488 | SCV004225094 | likely pathogenic | not provided | 2023-05-04 | criteria provided, single submitter | clinical testing | PP2, PP3, PM1, PM2, PM5, PS4_moderate |