Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Athena Diagnostics Inc | RCV000518259 | SCV000614279 | pathogenic | not provided | 2022-03-21 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with CADASIL. 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. |
Centre for Mendelian Genomics, |
RCV001197703 | SCV001368482 | likely pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2020-02-21 | criteria provided, single submitter | clinical testing | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_MOD,PM1,PM2,PP2,PP3. |
Invitae | RCV000518259 | SCV002246398 | pathogenic | not provided | 2022-09-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 447830). This variant is also known as R1075C. This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 11571335, 12861102, 15827866, 15834039, 22878905; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the NOTCH3 protein (p.Arg1076Cys). |
Ce |
RCV000518259 | SCV002585721 | likely pathogenic | not provided | 2022-09-01 | criteria provided, single submitter | clinical testing | NOTCH3: PM1:Strong, PM2, PS4:Moderate, PP2 |