Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000711010 | SCV000841326 | pathogenic | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | This variant has been identified in multiple unrelated individuals 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). |
| Institute of Medical Genetics and Applied Genomics, |
RCV003106028 | SCV003761555 | pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2023-01-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000711010 | SCV005837880 | pathogenic | not provided | 2024-05-23 | 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 251 of the NOTCH3 protein (p.Cys251Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 12395806, 22664156; external communication). ClinVar contains an entry for this variant (Variation ID: 585613). 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.Cys251 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14710716, 28534048; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |