Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812475 | SCV001472174 | likely pathogenic | not provided | 2019-08-25 | criteria provided, single submitter | clinical testing | The NOTCH3 c.3084G>C; p.Trp1028Cys variant, to our knowledge, is not reported in the medical literature or gene specific databases. However, a different nucleotide change (c.3084G>T) causing the same Trp1028Cys alteration, is reported in the literature in an individual with CADASIL (Testi 2012 Supplemental Table 4, Viana-Baptista 2007). The p.Trp1028Cys variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tryptophan at codon 1028 is a highly conserved residue within an EGF-like calcium-binding domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, 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 Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Testi S et al. Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Sci. 2012 Aug 15;319(1-2):37-41. Viana-Baptista et al. Cerebrovasc Dis. 2007. 23S2 75. Accessed online: https://www.karger.com/Article/Pdf/103854 |
| Labcorp Genetics |
RCV001812475 | SCV002112358 | uncertain significance | not provided | 2022-06-05 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 993757). This missense change has been observed in individual(s) with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (PMID: 32582863). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1028 of the NOTCH3 protein (p.Trp1028Cys). |