ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.7252T>A (p.Trp2418Arg) (rs780437384)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489209 SCV000577060 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The W2418R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The W2418R variant is observed in 6/66684 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with nemaline myopathy (Stenson et al., 2014).
Invitae RCV000559394 SCV000640855 uncertain significance Nemaline myopathy 2 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 2418 of the NEB protein (p.Trp2418Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs780437384, ExAC 0.009%). This variant has not been reported in the literature in individuals with a NEB-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: "unavailable"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NEB function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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