ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.9578A>G (p.Glu3193Gly) (rs369985728)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482607 SCV000574207 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing The E3193G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E3193G variant is not observed at a significant frequency in large population cohorts (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; 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). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV001060155 SCV001224827 uncertain significance Nemaline myopathy 2 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 3193 of the NEB protein (p.Glu3193Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs369985728, ExAC 0.02%). This variant has not been reported in the literature in individuals with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 424402). 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: "Not Available"; 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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