ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2576C>T (p.Thr859Met) (rs199505287)

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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 RCV000621614 SCV000739513 uncertain significance Cardiovascular phenotype 2017-12-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000655238 SCV000777168 uncertain significance Adams-Oliver syndrome 5 2017-09-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 859 of the NOTCH1 protein (p.Thr859Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs199505287, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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