ClinVar Genomic variation as it relates to human health

The NOTCH3 c.437G>A; p.Cys146Tyr variant (rs1236699193) is reported in the literature in multiple individuals affected with CADASIL and co-segregates with disease in a large family (Fattapposta 2004, Malandrini 2002, Parisi 2003). This variant is found on a single chromosome in the Genome Aggregation Database (1/243010 alleles), indicating it is not a common polymorphism. The cysteine at codon 146 is highly conserved, it occurs in the third 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.Cys146Tyr variant is consistent with the predominant mechanism of disease in NOTCH3. Additionally, other amino acid substitutions at this codon (p.Cys146Arg, p.Cys146Trp) have been reported in individuals with CADASIL and are considered disease-causing (Mizuta 2017, Joutel 1997). Based on available information, the p.Cys146Tyr variant is considered to be pathogenic. References: Fattapposta F et al. Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI. Funct Neurol. 2004 Oct-Dec;19(4):239-42. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Malandrini A et al. Asymptomatic cores and paracrystalline mitochondrial inclusions in CADASIL. Neurology. 2002 Aug 27;59(4):617-20. Mizuta I et al. New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan. J Neurol Sci. 2017 Oct 15;381:62-67. Parisi V et al. Early visual function impairment in CADASIL. Neurology. 2003 Jun 24;60(12):2008-10. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603.

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 CADASIL. 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 146 of the NOTCH3 protein (p.Cys146Tyr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 15776792). ClinVar contains an entry for this variant (Variation ID: 447849). 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%. This variant disrupts the p.Cys146 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9388399, 18948701, 20935329). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant interpreted as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1012. 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.