ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.12018+1G>A (rs762278237)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254952 SCV000322455 likely pathogenic not provided 2019-12-24 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); The c.12018+1 G>A variant has been reported previously in the presence of a second NEB variant, in two unrelated individual with nemaline myopathy, however, no other phenotypic or family information was available (Lehtokari et al., 2014); This variant is associated with the following publications: (PMID: 25205138, 31589614)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000254952 SCV000704802 pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing
Invitae RCV000593350 SCV000832679 pathogenic Nemaline myopathy 2 2017-11-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 80 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs762278237, ExAC 0.003%). This variant has been reported in two families affected with autosomal recessive nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 265494). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and 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 RCV000593350 SCV001164420 likely pathogenic Nemaline myopathy 2 2018-12-03 criteria provided, single submitter research The heterozygous c.12018+1G>A variant in NEB was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nemaline myopathy. This variant has been reported in the compound heterozygous state, with a splice site variant and a frameshift variant, in two additional, unrelated individuals (PMID: 25205138). The presence of this variant in combination with a reported pathogenic variant and in several individual with nemaline myopathy increases the likelihood that the c.12018+1G>A variant is pathogenic. This variant has been identified in 0.002981% (1/33548) of Latino chromosomes and 0.001798% (2/111260) of European (non-Finnish) chromsomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762278237). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The c.12018+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to remove a splicing site, causing abnormal splicing that does not result in a frameshift in the reading frame. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, the c.12018+1G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3_Strong (Richards 2015).
Counsyl RCV000593350 SCV001132440 pathogenic Nemaline myopathy 2 2016-12-28 no assertion criteria provided clinical testing
Genomics England Pilot Project,Genomics England RCV000593350 SCV001760060 pathogenic Nemaline myopathy 2 no assertion criteria provided clinical testing

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