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

Total submissions: 3

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.