ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4313G>A (p.Arg1438His) (rs61751541)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619426 SCV000739409 uncertain significance Cardiovascular phenotype 2016-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000766059 SCV000897515 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000461782 SCV000548935 uncertain significance Adams-Oliver syndrome 5 2016-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1438 of the NOTCH1 protein (p.Arg1438His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs61751541, ExAC 0.02%) but has not been reported in the literature in individuals with a 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. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, 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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