ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6895G>A (p.Gly2299Ser) (rs1020747496)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521367 SCV000622002 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The G2299S 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). The G2299S 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. In addition, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000552480 SCV000659486 uncertain significance Adams-Oliver syndrome 5 2017-01-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2299 of the NOTCH1 protein (p.Gly2299Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. 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 (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 novel 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.

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