ClinVar Genomic variation as it relates to human health

PP2, PP4, PM1, PS4

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features of CADASIL. This variant occurs as the most likely explanation for disease in a significant number of 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 variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1021 of the NOTCH3 protein (p.Tyr1021Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 18803652, 21786151, 31998484, 32277177). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic.

The NOTCH3 c.3062A>G; p.Tyr1021Cys variant (rs1167405466) is reported in the literature in several individuals affected with CADASIL (Hu 2021, Kalimo 2002, Mukai 2020, Pantoni 2010, Petrea 2019, Piccirillo 2008, Uppal 2019). This variant is also reported in ClinVar (Variation ID: 447825). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.658). However, this variant occurs in an EGF-like domain, and 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: Hu Y et al. NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients. Front Genet. 2021 Jul 15;12:705284. PMID: 34335700. Kalimo H et al. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol. 2002 Jul;12(3):371-84. PMID: 12146805. Mukai M et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020 Aug;65(8):637-646. PMID: 32277177. 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. PMID: 20038773. Petrea RE et al. Novel Neuroimaging "Encephalitic-Like Brain MRI Phenotype" in a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Acta Sci Neurol. 2019 Dec 9;3(1):03-08. 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. PMID: 18803652. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. PMID: 24844136. Uppal M et al. CADASIL presenting as late-onset mania with anosognosia. Clin Case Rep. 2019 Dec 8;8(1):47-50. PMID: 31998484.

Reported previously in the heterozygous state in individuals with clinical features of CADASIL (PMID: 12146805, 18803652, 20038773, 32765252, 31998484, 34335700, 35775048; Ivan Tourtourikov et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37873835, 22878905, 15995828, 18803652, 20038773, 22367627, 21786151, 32765252, 32912545, 35754959, 34335700, 31998484, Ivan2021[Article], 37476306, Uemura_2022, 35775048, 30956055, 32277177, 12146805, 24844136)

The NOTCH3 c.3062A>G variant is predicted to result in the amino acid substitution p.Tyr1021Cys. This variant has been reported to be causative for CADASIL in several unrelated individuals (Kalimo et al. 2002. PubMed ID: 12146805; Pantoni et al. 2010. PubMed ID: 20038773). Of note, the vast majority of CADASIL-causing missense variants in the NOTCH3 gene result in the gain or loss of cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant adds a cysteine residue and is located in the extracellular EGF-like domain 26. Pathogenic variants in EGF domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGF domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). At PreventionGenetics, we have previously identified this variant in other affected individuals. Taken together, we interpret this variant as pathogenic.

Variant interpreted as Likely pathogenic and reported on 10-06-2017 by lab or GTR ID Fulgent. GenomeConnect - CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.