Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812344 | SCV001471483 | likely pathogenic | not provided | 2020-06-09 | criteria provided, single submitter | clinical testing | The NOTCH3 c.239A>G; p.Asp80Gly variant is reported in the literature in a family affected with CADASIL and co-segregated with disease in four affected relatives (Wollenweber 2015). Although the diagnosis of this family was questioned by one group (Rutten 2015), the clinical presentation, MRI profiles, and pathology results from affected family members were judged by other groups to be highly consistent with a specific diagnosis of CADASIL (Wollenweber 2015, Muino 2017). The p.Asp80Gly variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 80 is highly conserved, it occurs in the second EGF-like domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. While most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), the p.Asp80Gly variant does not involve a cysteine residue. However, functional studies suggest the p.Asp80Gly variant protein forms multimers or aggregates at a similar rate to known CADASIL-associated, cysteine-affecting variants (Wollenweber 2015), suggesting it may function through the same mechanism by which other pathogenic NOTCH3 variants are thought to cause disease (Muino 2017). Based on available information, the p.Asp80Gly variant is considered to be likely pathogenic. 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. Rutten J et al. Letter by Rutten et al Regarding Article, "Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro". Stroke. 2015;46(6):e153. Wollenweber FA et al. Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro. Stroke. 2015;46(3):786-792. |
| Invitae | RCV001812344 | SCV004297948 | uncertain significance | not provided | 2024-01-26 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 80 of the NOTCH3 protein (p.Asp80Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 24840674, 25604251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 993546). 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 80%. Experimental studies have shown that this missense change affects NOTCH3 function (PMID: 25604251). 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. |