ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3341G>A (p.Arg1114His) (rs777684045)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521074 SCV000621527 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The R1114H variant has not been published as pathogenic or been reported as benign to our knowledge. The R1114H variant was observed in 9/30738 alleles (0.03%) from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). R1114H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species; histidine is the wild type amino acid at this position in multiple species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000818617 SCV000959239 uncertain significance Adams-Oliver syndrome 5 2019-03-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1114 of the NOTCH1 protein (p.Arg1114His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs777684045, ExAC 0.02%). This variant has not been reported in the literature in individuals with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452700). 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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