Submissions for variant NM_001164508.2(NEB):c.24666del (p.Phe8222fs)

dbSNP: rs794727136

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000262527	SCV000329692	pathogenic	not provided	2020-07-20	criteria provided, single submitter	clinical testing	Frameshift 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 (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000670684	SCV001232114	pathogenic	Nemaline myopathy 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe8257Leufs*10) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 279999). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000262527	SCV002018280	pathogenic	not provided	2019-07-08	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000670684	SCV002515307	likely pathogenic	Nemaline myopathy 2	2022-02-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000670684	SCV003761209	likely pathogenic	Nemaline myopathy 2	2023-01-24	criteria provided, single submitter	curation	The heterozygous p.Phe8257LeufsTer10 variant in NEB was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000002.12:g.151612184A>T), in one individual with nemaline myopathy. Trio exome analysis showed that this variant was in trans with a variant of uncertain significance (NC_000002.12:g.151612184A>T). The p.Phe8222fs variant has not been previously reported in the literature in individuals with nemaline myopathy 2 but has been identified in 0.004% (3/82708) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs794727136). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 279999) and has been interpreted as pathogenic by GeneDx, Invitae, Natera, Inc, and PerkinElmer Genomics and as likely pathogenic by Counsyl and the Daryl Scott Lab of the Baylor College of Medicine. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 8222 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for nemaline myopathy 2. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).
Baylor Genetics	RCV003469212	SCV004200121	likely pathogenic	Arthrogryposis multiplex congenita 6	2023-09-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000670684	SCV000795570	likely pathogenic	Nemaline myopathy 2	2017-11-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000670684	SCV001459162	pathogenic	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing