Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000518409 | SCV000614216 | pathogenic | not provided | 2020-03-19 | criteria provided, single submitter | clinical testing | The variant disrupts a cysteine residue in an EGF-like repeat domain, which is important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. |
| Institute of Medical Genetics and Applied Genomics, |
RCV000518409 | SCV001446484 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000518409 | SCV002286836 | pathogenic | not provided | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 421 of the NOTCH3 protein (p.Arg421Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 16009764; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 447779). 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%. For these reasons, this variant has been classified as Pathogenic. |