Submissions for variant NM_001164508.2(NEB):c.12160del (p.Trp4054fs)

dbSNP: rs1319778592

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792283	SCV000931569	pathogenic	Nemaline myopathy 2	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp4054Glyfs*12) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 639479). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004569503	SCV005052168	pathogenic	Arthrogryposis multiplex congenita 6	2023-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702421	SCV005203605	pathogenic	Nemaline myopathy	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: NEB c.12160delT (p.Trp4054GlyfsX12) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 248972 control chromosomes. c.12160delT has been reported in the literature in at least one individual affected with Nemaline Myopathy (e.g. Lehtokari_2014). These data suggest the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 639479). Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004702421	SCV005907881	likely pathogenic	Nemaline myopathy	2025-03-11	criteria provided, single submitter	curation	The p.Trp4054GlyfsTer12 variant in NEB has been reported in one individual with nemaline myopathy (PMID: 25205138), and has been identified in 0.003% (1/33480) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1319778592). 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: 639479) and has been interpreted as pathogenic by Invitae and Natera Inc. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 4045 and leads to a premature termination codon 12 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_suppoting (Richards 2015).
Natera, Inc.	RCV000792283	SCV001459395	pathogenic	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing