Submissions for variant NM_001164508.2(NEB):c.24454C>T (p.Arg8152Ter)

dbSNP: rs763364977

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586673	SCV000697819	pathogenic	Nemaline myopathy	2016-07-28	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.24559C>T (p.Arg8187X) variant causes a nonsense mutation involving a conserved nucleotide resulting in a truncated NEB protein, a known mechanism for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals in the compound heterozygous state. Publications have indicated that the variant of interest could cause a intermediate phenotype. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476276	SCV000893561	pathogenic	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2024-02-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763063	SCV000915863	likely pathogenic	Nemaline myopathy 2	2018-10-16	criteria provided, single submitter	clinical testing	The NEB c.18886C>T (p.Arg6296Ter) variant, also reported as c.24559C>T (p.Arg8187Ter), is a stop-gained variant predicted to result in a premature termination of the protein. The p.Arg8187Ter variant is reported in two studies, in which it is found in two patients in a compound heterozygous state with nemaline myopahty (Lehtokari et al. 2014; Piga et al. 2016). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage, thus the variant is presumed to be rare. Based on the evidence and potential impact of stop-gained variants, the p.Arg6296Ter variant is classified as likely pathogenic for autosomal recessive nemaline myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763063	SCV000953578	pathogenic	Nemaline myopathy 2	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg8187*) 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: 25205138, 27105866). ClinVar contains an entry for this variant (Variation ID: 496135). 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.
Revvity Omics, Revvity	RCV001783093	SCV002018288	pathogenic	not provided	2021-03-05	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001783093	SCV002818223	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000763063	SCV004807129	pathogenic	Nemaline myopathy 2	2024-03-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568306	SCV005052098	pathogenic	Arthrogryposis multiplex congenita 6	2024-02-15	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000586673	SCV005907779	likely pathogenic	Nemaline myopathy	2025-02-25	criteria provided, single submitter	curation	The p.Arg8152Ter variant in NEB has been reported in three individuals with nemaline myopathy (PMID: 36703223, 25205138, 27105866), and has been identified in 0.001% (1/90592) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs763364977). 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: 496135) and has been interpreted as pathogenic or likely pathogenic by many submitters. Of the 3 affected individuals ,1 of those was a homozygote, which increases the likelihood that the p.Arg8152Ter variant is pathogenic (PMID: 36703223). This nonsense variant leads to a premature termination codon at position 8152, which is predicted to lead to a truncated or absent protein. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is in an in-frame exon and is more likely to escape (NMD) and result in a truncated protein. In-frame exon skipping 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).
Counsyl	RCV000763063	SCV001132439	pathogenic	Nemaline myopathy 2	2016-11-18	no assertion criteria provided	clinical testing