ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.2639G>A (p.Arg880His) (rs202026890)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520535 SCV000620997 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing The c.2639 G>A variant in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.2639 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.2639 G>A may create a cryptic splice acceptor site in exon 28 that could supplant the natural splice acceptor site. However, in the absence of RNA/functional studies, the actual effect of the c.2639 G>A change in this individual is unknown. If c.2639 G>A does not alter splicing, it will result in the R880H missense change.The R880H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. We interpret c.2639 G>A as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780537 SCV000917876 uncertain significance not specified 2018-06-11 criteria provided, single submitter clinical testing Variant summary: NEB c.2639G>A (p.Arg880His) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 65270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2639G>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001036252 SCV001199604 uncertain significance Nemaline myopathy 2 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 880 of the NEB protein (p.Arg880His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs202026890, 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: 452209). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. RCV001036252 SCV001455515 uncertain significance Nemaline myopathy 2 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.