Submissions for variant NM_001164508.2(NEB):c.24588C>G (p.Tyr8196Ter)

gnomAD frequency: 0.00003  dbSNP: rs754272530

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498615	SCV000590584	pathogenic	not provided	2024-09-13	criteria provided, single submitter	clinical testing	Observed with a second pathogenic variant in two siblings affected with congenital myopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29382405); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34758253, 29382405)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670685	SCV000832909	pathogenic	Nemaline myopathy 2	2024-02-06	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. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs754272530, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 29382405). This variant is also known as c.24588C>G (p.Tyr8196*). ClinVar contains an entry for this variant (Variation ID: 432817). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Baylor Genetics	RCV003470620	SCV004198180	pathogenic	Arthrogryposis multiplex congenita 6	2023-12-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000670685	SCV000795571	likely pathogenic	Nemaline myopathy 2	2017-11-09	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000670685	SCV001760059	pathogenic	Nemaline myopathy 2		no assertion criteria provided	clinical testing