ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.21076C>T (p.Arg7026Ter) (rs769345284)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000170577 SCV000222673 likely pathogenic Non-immune hydrops fetalis 2013-12-15 criteria provided, single submitter research
Counsyl RCV000664706 SCV000788710 pathogenic Nemaline myopathy 2 2017-01-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781653 SCV000919865 pathogenic Nemaline myopathy 2018-05-14 criteria provided, single submitter clinical testing Variant summary: NEB c.21076C>T (p.Arg7026X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.24407_24410dupTGTT, p.Leu8137fsX18; c.24559C>T, p.Arg8187X). The variant allele was found at a frequency of 3.3e-05 in 244554 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (3.3e-05 vs 0.0035), allowing no conclusion about variant significance. The variant, c.21076C>T, has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Lehtokari_2014, Oliveira_2016, Park_2018), as well as in a family with recurrent fetal loss in the homozygous state (Shamseldin_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000664706 SCV001377024 pathogenic Nemaline myopathy 2 2019-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg7026*) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs769345284, ExAC 0.003%). This variant has been observed in individuals affected with nemaline myopathy (PMID: 26841830, 25205138). ClinVar contains an entry for this variant (Variation ID: 190457). Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000664706 SCV001463299 pathogenic Nemaline myopathy 2 2020-09-16 no assertion criteria provided clinical testing

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