ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.6092G>A (p.Arg2031His)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286594 SCV001473194 uncertain significance none provided 2019-07-23 criteria provided, single submitter clinical testing The NOTCH3 c.6092G>A; p.Arg2031His variant (rs779314594), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.006% (15/259256 alleles) in the Genome Aggregation Database. The arginine at codon 2031 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.Arg2031His 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. 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.
Athena Diagnostics Inc RCV001288544 SCV001475724 likely benign not provided 2020-02-19 criteria provided, single submitter clinical testing

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