ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.1235A>G (p.Gln412Arg) (rs1131691934)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494568 SCV000583173 likely pathogenic not provided 2015-09-08 criteria provided, single submitter clinical testing The Q412R variant in the NOTCH3 gene has not been published as a pathogenic variant nor has it been reported as a benign polymorphism to our knowledge. The Q412R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q412R variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved in mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (S414C, G420C, R421C) have been reported in the Human Gene Mutation Database in association with CADASIL (Stenson et al., 2014), supporting the functional importance of this region of the protein. The Q412R variant is a strong candidate for a disease-causing variant,however, the possibility it may be a rare benign variant cannot be excluded.

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