Submissions for variant NM_001164508.2(NEB):c.25141_25142del (p.Met8381fs)

gnomAD frequency: 0.00001  dbSNP: rs1472403020

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000598513	SCV000709506	pathogenic	not provided	2017-06-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531111	SCV003032014	pathogenic	Nemaline myopathy 2	2022-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 502672). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met8416Aspfs*2) 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).
Baylor Genetics	RCV003465348	SCV004200113	likely pathogenic	Arthrogryposis multiplex congenita 6	2024-02-05	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV004698844	SCV005200924	likely pathogenic	NEB-related disorder	2024-04-10	criteria provided, single submitter	clinical testing	PVS1, PM2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV005252988	SCV005907770	likely pathogenic	Nemaline myopathy	2025-02-24	criteria provided, single submitter	curation	The p.Met8381Aspfs variant in NEB has not been previously reported in the literature in individuals with nemaline myopathy, but has been identified in 0.001% (1/74494) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1472403020). 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: 502672 ) and has been interpreted as pathogenic by Eurofins Ntd Llc (ga) and Invitae, and likely pathogenic by Baylor Genetics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 8381 and leads to a premature termination codon 2 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 autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015).