ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.24693C>G (p.Tyr8231Ter) (rs754272530)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498615 SCV000590584 pathogenic not provided 2017-06-19 criteria provided, single submitter clinical testing The Y8231X pathogenic variant in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y8231X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret Y8231X as a pathogenic variant.
Invitae RCV000670685 SCV000832909 pathogenic Nemaline myopathy 2 2019-11-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr8231*) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs754272530, ExAC 0.006%). This variant has been observed in a family with clinical features of nemaline myopathy (PMID: 29382405). This variant is also known as c.24588C>G (p.Tyr8196*) in the literature. ClinVar contains an entry for this variant (Variation ID: 432817). Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000670685 SCV001164419 pathogenic Nemaline myopathy 2 2018-12-03 criteria provided, single submitter research The heterozygous p.Tyr8196Ter variant in NEB was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with nemaline myopathy. The presence of this variant in combination with a likely pathogenic variant and in an individual with nemaline myopathy increases the likelihood that the p.Tyr8196Ter variant is pathogenic. This variant has been identified in 0.005516% (5/90638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754272530). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 8196, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, this variant meets criteria to be classified as pathogenic for nemaline myopathy an autosomal recessive manner based on the predicted impact of the variant and occurrence with a likely pathogenic in an individual with nemaline myopathy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015).
Counsyl RCV000670685 SCV000795571 likely pathogenic Nemaline myopathy 2 2017-11-09 no assertion criteria provided clinical testing

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