ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.2108G>A (p.Arg703His) (rs561126575)

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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 RCV000618346 SCV000739354 uncertain significance Cardiovascular phenotype 2016-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
ITMI RCV000121662 SCV000085860 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000544874 SCV000659391 uncertain significance Adams-Oliver syndrome 5 2017-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 703 of the NOTCH1 protein (p.Arg703His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs561126575, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 134912). 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 histidine 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 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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