ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5224G>T (p.Ala1742Ser) (rs760669267)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428861 SCV000536587 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The A1742S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015). The A1742S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position where amino acids with similar properties to alanine are tolerated across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000471204 SCV000548919 uncertain significance Adams-Oliver syndrome 5 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1742 of the NOTCH1 protein (p.Ala1742Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs760669267, 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it 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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