ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3062A>G (p.Tyr1021Cys) (rs1167405466)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518485 SCV000614273 pathogenic not provided 2021-03-08 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic mutations associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
GeneDx RCV000518485 SCV000779642 likely pathogenic not provided 2021-04-05 criteria provided, single submitter clinical testing Reported previously in the heterozygous state in individuals with clinical features of CADASIL (Kalimo et al., 2002; Piccirillo et al., 2008; Pantoni et al., 2010; Shindo et al., 2020); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30956055, 12146805, 22878905, 15995828, 18803652, 20038773, 22367627, 21786151, 32765252, 32912545, 32277177)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287827 SCV001474559 likely pathogenic none provided 2020-04-14 criteria provided, single submitter clinical testing The NOTCH3 c.3062A>G; p.Tyr1021Cys variant (rs1167405466) is reported in the literature in several individuals affected with CADASIL (Kalimo 2002, Pantoni 2010, Piccirillo 2008). This variant is found on a single chromosome in the Genome Aggregation Database (1/31374 alleles), indicating it is not a common polymorphism. The tyrosine at codon 1021 is highly conserved and occurs in the 26th EGF-like domain, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Still, 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.Tyr1021Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be likely pathogenic. References: Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. Pantoni L et al. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology. 2010 Jan 5;74(1):57-63. Piccirillo G et al. Increased QT variability in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Eur J Neurol. 2008 Nov;15(11):1216-21. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.
Invitae RCV000518485 SCV001583422 pathogenic not provided 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1021 of the NOTCH3 protein (p.Tyr1021Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 21786151, 18803652, external communication). ClinVar contains an entry for this variant (Variation ID: 447825). 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. For these reasons, this variant has been classified as Pathogenic.

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.