Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV001657989 | SCV001879559 | pathogenic | not provided | 2021-04-15 | 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. 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). |
| DASA | RCV000201951 | SCV002011894 | pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2021-09-02 | criteria provided, single submitter | clinical testing | The c.1187C>G;p.(Ser396Cys) variant has been published as a pathogenic variant in individuals affected with CADASIL, described with possible effect founder in italian population (PMID: 22664156; GeneOne, DASA) and ClinVar contains an entry for this variant (Variation ID: 217882) - PS4; variant is located in a mutational hot spot and/or critical and well-established functional domain - PM1; this variant is not present in population databases (rs863225297 - gnomAD no frequency; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2; this variant has been observed to segregate in ten italian families (PMID: 22664156) - PP1_strong; missense variant in NOTCH3 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2; in silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic. |
| Invitae | RCV001657989 | SCV002152259 | pathogenic | not provided | 2023-03-02 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217882). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 396 of the NOTCH3 protein (p.Ser396Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 22664156, 32277177; Invitae). |
| Mendelics | RCV000201951 | SCV000256878 | pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2014-07-25 | no assertion criteria provided | clinical testing |