ClinVar

Description

The NOTCH3 c.421C>T variant is predicted to result in the amino acid substitution p.Arg141Cys. The NOTCH3 gene sequence variant c.421C>T is predicted to result in the amino acid substitution p.Arg141Cys. This variant has been reported as causative for CADASIL in numerous unrelated patients, and functional studies support its pathogenicity (see, for example, Joutel et al. Lancet. 1997. PubMed ID: 9388399; Karlström et al. 2002. PubMed ID: 12482954; Cappelli et al. 2009. PubMed ID: 19576955). At PreventionGenetics, we previously identified this variant in other patients with a diagnosis of CADASIL. 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 three. 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 (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). We classify this variant as pathogenic.