ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3658C>T (p.Arg1220Trp) (rs115872852)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000878820 SCV001021795 likely benign not provided 2018-06-06 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000878820 SCV001143381 benign not provided 2019-05-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285636 SCV001472101 uncertain significance none provided 2020-08-07 criteria provided, single submitter clinical testing 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.

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.