ClinVar

Description

Variant summary: NOTCH3 c.1630C>T (p.Arg544Cys) results in a non-conservative amino acid change at a location bordered between the EGFR-13 and EGFR-14 domains (IPR000742) of the encoded protein sequence. This is different from other cysteine involving mutations residing within an EGFR domain and therefore, comparing with other cysteine-involving NOTCH3 mutations, R544C may result in a milder conformational change of NOTCH3 molecules and consequently a milder clinical phenotype (Liao_2015). Gain/loss of cysteine residues in the EGFr domains in NOTCH3 have been shown to be typical mutations of CADASIL and NOTCH3-related disorders (reviewed by Mizuno_2020). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 250312 control chromosomes, particularly at a frequency of 0.0041 within the East Asian subpopulation in the gnomAD database. c.1630C>T has been reported in the literature in multiple individuals/families (mainly of East Asian origin) affected with CADASIL and NOTCH3-Related Disorders (example: Oberstein_1999, Kim_2006, Soong_2013, Liao_2015). Asymptomatic individuals with the variant have also been reported within affected families (example: Kim_2006, Liao_2015). Recent data suggest that CADASIL is much more prevalent than previously suspected and the NOTCH3 clinical spectrum must be considerably broader, ranging from classic CADASIL to a much milder small-vessel disease, or possibly even non-penetrance (Hack RJ, Rutten J, Lesnik Oberstein SAJ. CADASIL. 2000 Mar 15 [Updated 2019 Mar 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed this variant since 2014: four have classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.