ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.3084G>C (p.Trp1028Cys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285698 SCV001472174 likely pathogenic none 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

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