ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.25441C>T (p.Arg8481Ter) (rs200731870)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520480 SCV000617715 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The R8481X variant in the NEB gene has been reported previously in a family with nemaline myopathy who also harbored a NEB frameshift variant, although the phase of the two variants was not specified (Lehtokari et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R8481X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R8481X as a pathogenic variant.
Invitae RCV000665375 SCV000935490 pathogenic Nemaline myopathy 2 2019-11-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg8481*) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200731870, ExAC 0.02%). This variant has been observed in an individual affected with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 449500). Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001174690 SCV001337942 pathogenic Nemaline myopathy 2020-01-13 criteria provided, single submitter clinical testing Variant summary: NEB c.25441C>T (p.Arg8481X) 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. The variant allele was found at a frequency of 3.2e-05 in 248620 control chromosomes. c.25441C>T has been reported in the literature in at-least two individuals affected with Nemaline Myopathy (Lehtokari_2014) and congenital core-rod myopathy (Wunderlich_2018) respectively. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000665375 SCV000789488 likely pathogenic Nemaline myopathy 2 2017-02-02 no assertion criteria provided clinical testing

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