Submissions for variant NM_001164508.2(NEB):c.24189_24192dup (p.Glu8065fs)

dbSNP: rs1553555882

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641338	SCV000762979	pathogenic	Nemaline myopathy 2	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu8100Serfs*5) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 12207938, 19805734, 26403434). ClinVar contains an entry for this variant (Variation ID: 533994). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192994	SCV001361492	pathogenic	Nemaline myopathy	2019-11-14	criteria provided, single submitter	clinical testing	Variant summary: NEB c.24294_24297dupTCAA (p.Glu8100SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 157122 control chromosomes (gnomAD). c.24294_24297dupTCAA has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Nemaline Myopathy 2 (Lehtokari_2014, Oliveira_2016, Pelin_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia	RCV000641338	SCV001423827	pathogenic	Nemaline myopathy 2		criteria provided, single submitter	clinical testing
Mendelics	RCV000641338	SCV002517766	pathogenic	Nemaline myopathy 2	2022-05-04	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252188	SCV002523768	pathogenic	See cases	2020-08-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PM3
GeneDx	RCV002282280	SCV002571407	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Reported in individuals with core-rod myopathy who also harbored a second NEB variant (Lehtokari et al., 2014; Malfatti et al., 2015); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33084218, 12207938, 26841830, 19805734, 25205138, 16917880, 26403434)
Baylor Genetics	RCV003465403	SCV004200264	pathogenic	Arthrogryposis multiplex congenita 6	2024-02-05	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV000641338	SCV005038603	pathogenic	Nemaline myopathy 2	2024-03-01	criteria provided, single submitter	research	PVS1+PP1_Strong+PM2
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000641338	SCV005051885	likely pathogenic	Nemaline myopathy 2	2024-02-01	criteria provided, single submitter	curation
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001192994	SCV005907787	likely pathogenic	Nemaline myopathy	2025-02-26	criteria provided, single submitter	curation	The p.Glu8065SerfsTer5 variant in NEB has been reported in at least four individuals with nemaline myopathy (PMID: 12207938, 33084218, 36233295), and has been identified in 0.006% (3/50984) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1553555882). 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: 533994) and has been interpreted as pathogenic by multiple submitters. Of the 4 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic/likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Glu8065SerfsTer5variant is pathogenic (Variation ID: 1213189; PMID: 25205138, 35175440). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 8065 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Computational tools predict a splicing impact, though this information is not predictive enough to determine/rule out pathogenicity. This variant is in an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated 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_strong, PM3, PM2_supporting (Richards 2015).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000641338	SCV006075095	pathogenic	Nemaline myopathy 2	2023-12-06	criteria provided, single submitter	clinical testing	PVS1,PP5,PM2