ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3356G>A (p.Cys1119Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1266914122
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
Athena Diagnostics RCV000516959 SCV000614283 pathogenic not provided 2020-08-12 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000516959 SCV001474558 likely pathogenic not provided 2019-11-07 criteria provided, single submitter clinical testing The NOTCH3 c.3356G>A; p.Cys1119Tyr variant (rs1266914122) is reported in the literature in at least one individual affected with CADASIL (Kim 2014). This variant is reported in ClinVar (Variation ID: 447834), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 1119 is highly conserved, 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). Based on available information, this variant is considered to be likely pathogenic. References: Kim YE et al. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging. 2014 Mar;35(3):726.e1-6. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Labcorp Genetics (formerly Invitae), Labcorp RCV000516959 SCV004523860 uncertain significance not provided 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1119 of the NOTCH3 protein (p.Cys1119Tyr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical feature of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 24139282, 31719132, 31915071). ClinVar contains an entry for this variant (Variation ID: 447834). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.