ClinVar

Description

The NOTCH3 c.3658C>T; p.Arg1220Trp variant (rs115872852), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 707700). This variant is found in the African population with an allele frequency of 0.12% (30/24834 alleles) in the Genome Aggregation Database. The arginine at codon 1220 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Although the p.Arg1220Trp does not involve a cysteine residue, due to the lack of clinical and functional data, its clinical significance is uncertain. References: Muino E et al. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int J Mol Sci. 2017 Sep 13;18(9). pii: E1964. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.