ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4880G>A (p.Arg1627His) (rs946083212)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460526 SCV000548949 uncertain significance Adams-Oliver syndrome 5 2016-04-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1627 of the NOTCH1 protein (p.Arg1627His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency) and 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 output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is also 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 novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825645 SCV000967015 uncertain significance not specified 2017-08-29 criteria provided, single submitter clinical testing The p.Arg1627His (NM_017617.3 c.4880G>A) variant in NOTCH1 has not been previous ly reported in individuals with congenital heart disease. This variant has been identified in 1/12274 of East Asian chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs946083212). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p .Arg1627 variant is uncertain.

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