ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.895A>T (p.Ser299Cys)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289863 SCV001477862 likely pathogenic none provided 2019-10-17 criteria provided, single submitter clinical testing The NOTCH3 c.895A>T; p.Ser299Cys variant is reported in the literature in an individual with symptoms of CADASIL but not typical MRI findings, possibly due to young age (Golomb 2004). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The serine at codon 299 is highly conserved, it occurs in an EGF-like domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Ser299Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Golomb MR et al. Recurrent hemiplegia, normal MRI, and NOTCH3 mutation in a 14-year-old: is this early CADASIL? Neurology. 2004 Jun 22;62(12):2331-2. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.