ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.25336C>T (p.Arg8446Ter)

gnomAD frequency: 0.00004  dbSNP: rs200731870
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520480 SCV000617715 pathogenic not provided 2022-09-30 criteria provided, single submitter clinical testing Reported in a family with nemaline myopathy who also harbored a NEB frameshift variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Lehtokari et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30467404, 25205138, 30057997, 34426522, 31589614, 31127727)
Labcorp Genetics (formerly Invitae), Labcorp RCV000665375 SCV000935490 pathogenic Nemaline myopathy 2 2024-01-15 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. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs200731870, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 449500). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Revvity Omics, Revvity RCV000520480 SCV002018257 pathogenic not provided 2019-11-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV003476221 SCV004200279 pathogenic Arthrogryposis multiplex congenita 6 2024-02-22 criteria provided, single submitter clinical testing
Counsyl RCV000665375 SCV000789488 likely pathogenic Nemaline myopathy 2 2017-02-02 no assertion criteria provided clinical testing
Natera, Inc. RCV000665375 SCV001459154 pathogenic Nemaline myopathy 2 2020-09-16 no assertion criteria provided clinical testing

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