Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000711006 | SCV000841322 | pathogenic | not provided | 2020-09-29 | 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. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to form Notch3 aggregates that are retained in the endoplasmic reticulum (ER) leading to impaired cell proliferation (PMID 19825845). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain. |
| Invitae | RCV000711006 | SCV003443278 | pathogenic | not provided | 2023-12-16 | 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 185 of the NOTCH3 protein (p.Cys185Arg). 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 (CADASIL) (PMID: 9388399, 30402942; Invitae). ClinVar contains an entry for this variant (Variation ID: 585609). 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%. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 19825845, 22079830). This variant disrupts the p.Cys185 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25033846, 28991717, 31443546, 32277177). 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. |