ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.19543C>T (p.Arg6515Cys) (rs765363585)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521082 SCV000618650 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEB gene. The R6515C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R6515C 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). The R6515C 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 across species, 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001243032 SCV001416162 uncertain significance Nemaline myopathy 2 2019-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 6515 of the NEB protein (p.Arg6515Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs765363585, ExAC 0.006%). This variant has not been reported in the literature in individuals with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 450107). 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001243032 SCV001440702 uncertain significance Nemaline myopathy 2 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.

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