ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3908G>A (p.Arg1303His) (rs768775024)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559743 SCV000659435 uncertain significance Adams-Oliver syndrome 5 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1303 of the NOTCH1 protein (p.Arg1303His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs768775024, ExAC 0.09%) 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. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000576544 SCV000678230 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2017-08-01 criteria provided, single submitter clinical testing NOTCH1 NM_017617 exon24 p.Arg1303His (c.3908G>A): This variant has not been reported in the literature but is present in 14/33164 Latino chromosomes in the Genome Aggregation Database ( Computational predictive tools suggest that this variant may not impact the protein. Of note, 5 other species carry a histidine (His) at this position, further suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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