ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5981A>G (p.Asp1994Gly) (rs1454512890)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519774 SCV000618635 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The D1994G variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1994G 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. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the D1994G variant lacks sufficient evidence, including observation in a significant number of affected individuals, segregation studies, and functional characterization, that would further clarify its potential pathogenicity.
Invitae RCV000531729 SCV000659473 uncertain significance Adams-Oliver syndrome 5 2017-07-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1994 of the NOTCH1 protein (p.Asp1994Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with 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 disruptive, but 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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