ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.5297T>C (p.Met1766Thr)

dbSNP: rs1420105350
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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 RCV001813082 SCV001473537 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing The NOTCH3 c.5297T>C; p.Met1766Thr variant (rs1420105350), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 1766 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Although the p.Met1766Thr variant does not occur within this critical region or involve a cysteine residue, due to its low population frequency and conservation, its clinical significance is uncertain at this time. 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.

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