Submissions for variant NM_001164508.2(NEB):c.24579G>A (p.Ser8193=)

dbSNP: rs202048855

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623853	SCV000742389	likely pathogenic	Inborn genetic diseases	2017-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820159	SCV000960858	pathogenic	Nemaline myopathy 2	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change affects codon 8228 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. This variant also falls at the last nucleotide of exon 175, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202048855, gnomAD 0.006%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 24725366; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.24579G>A. ClinVar contains an entry for this variant (Variation ID: 521691). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
3billion	RCV000820159	SCV002058735	likely pathogenic	Nemaline myopathy 2	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000521691).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000034, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV000820159	SCV002060096	likely pathogenic	Nemaline myopathy 2	2021-11-12	criteria provided, single submitter	clinical testing	NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant classified as likely pathogenic in the context of NEB-related nemaline myopathy. S8228= has been observed in cases with relevant disease (PMID: 32222963, 25205138, 23726790, 26562614). Functional assessments of this variant are not available in the literature. S8228= has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_001271208.1(NEB):c.24684G>A(S8228=) is a silent variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV002506517	SCV002811097	pathogenic	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2021-07-27	criteria provided, single submitter	clinical testing
GeneDx	RCV003153763	SCV003842473	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Variant located in the final nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138, 32222963, 35081925, 29669168, 24725366)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000820159	SCV004046298	pathogenic	Nemaline myopathy 2		criteria provided, single submitter	clinical testing	This synonymous variant affects the last nucleotide of exon 174 of the NEB gene and is predicted to abolish the canonical splice donor site of intron 174 by in silico tools (MaxEntScan, GeneSplicer); however, to our knowledge, no RNA-base splicing analysis has been performed to clarify the effect of this alteration on splicing. This variant has been previously reported as a compound heterozygous change or together with another NEB variant, in patients with Nemaline Myopathy (PMID: 24725366, 30467404, 29669168). In one patient, electron microscopy studies showed elongated nemaline bodies in the perinuclear and/or subsarcolemmal areas of muscle fibres (PMID: 24725366). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003428% (8/233398) and thus is presumed to be rare. Based on the available evidence, the c.24579G>A (p.Ser8193=) variant is classified as Pathogenic.
Baylor Genetics	RCV003465358	SCV004200170	pathogenic	Arthrogryposis multiplex congenita 6	2024-03-29	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586841	SCV005038590	pathogenic	Nemaline myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PM1+PM2+PM3+PP3+PP4+PP5