ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4372G>A (p.Ala1458Thr) (rs200495793)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619622 SCV000739452 uncertain significance Cardiovascular phenotype 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000468014 SCV000548956 uncertain significance Adams-Oliver syndrome 5 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1458 of the NOTCH1 protein (p.Ala1458Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200495793, ExAC 0.04%) but has not been reported in the literature in individuals with a NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 409073). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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