ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.3853G>A (p.Val1285Met) (rs756972680)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519706 SCV000618910 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NOTCH1 gene. The V1285M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 11/120,448 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The V1285M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in silico analyses, including protein predictors and evolutionary conservation, is inconsistent as to whether this 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 RCV000693083 SCV000820938 uncertain significance Adams-Oliver syndrome 5 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1285 of the NOTCH1 protein (p.Val1285Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs756972680, ExAC 0.01%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID:450338). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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