Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Athena Diagnostics Inc | RCV000516299 | SCV000614268 | pathogenic | not provided | 2020-10-07 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3089G>A. This variant has been identified in at least one individual with clinical features associated with this gene. 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). |
Prevention |
RCV003403217 | SCV004110148 | pathogenic | NOTCH3-related condition | 2023-03-06 | criteria provided, single submitter | clinical testing | The NOTCH3 c.3011G>A variant is predicted to result in the amino acid substitution p.Cys1004Tyr. This variant was reported in an individual with CADASIL (Guerrot et al. 2008. PubMed ID: 18572291). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGF-like domain 26. Pathogenic variants in EGF-like domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGF-like domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic. |