ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.10118G>A (p.Arg3373Gln) (rs568814745)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520687 SCV000620356 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing The R3373Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3373Q variant is observed in 7/66,704 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Most reported pathogenic variants in the NEB gene are truncating/loss-of-function. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. However, this variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000557295 SCV000640477 uncertain significance Nemaline myopathy 2 2017-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3373 of the NEB protein (p.Arg3373Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs568814745, ExAC 0.06%). This variant has not been reported in the literature in individuals with 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Natera, Inc. RCV000557295 SCV001454949 uncertain significance Nemaline myopathy 2 2020-01-17 no assertion criteria provided clinical testing

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