Submissions for variant NM_001164508.2(NEB):c.23989C>T (p.Arg7997Ter)

gnomAD frequency: 0.00061  dbSNP: rs549794342

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414803	SCV000492632	likely pathogenic	Muscular dystrophy; Progressive proximal muscle weakness; Limb pain	2015-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000416049	SCV000493368	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	NEB: PVS1:Strong, PM2
GeneDx	RCV000416049	SCV000571535	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	Identified in a pregnancy loss with an unspecified fetal anomaly (PMID: 33100332); Nonsense 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; This variant is associated with the following publications: (PMID: 31980526, 32721234, 31589614, 33100332)
Invitae	RCV000576327	SCV000814554	pathogenic	Nemaline myopathy 2	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg8032*) 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 (rs549794342, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 373977). 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.
Fulgent Genetics, Fulgent Genetics	RCV002480270	SCV000893562	likely pathogenic	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2022-04-12	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000576327	SCV000996203	likely pathogenic	Nemaline myopathy 2	2018-10-04	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 168 of 182 is predicted to result in loss of normal protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (61/183470) and thus is presumed to be rare. This variant has been classified as likely pathogenic by several clinical diagnostic labs in the ClinVar database (Variation ID: 373977). Based on the available evidence, the c.23989C>T (p.Arg7997Ter) variant is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000576327	SCV001440128	pathogenic	Nemaline myopathy 2	2019-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000576327	SCV001525409	likely pathogenic	Nemaline myopathy 2	2019-10-01	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000416049	SCV002010589	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000416049	SCV002018290	pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576327	SCV002767185	pathogenic	Nemaline myopathy 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nemaline myopathy 2, autosomal recessive (MIM#256030). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). In silico splice site analysis of this variant may also result in activation of a cryptic 5' splice site resulting in a frameshift (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 62 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with nemaline myopathy 2, autosomal recessive (MIM#256030) (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155176	SCV003845106	likely pathogenic	Nemaline myopathy	2023-02-21	criteria provided, single submitter	clinical testing	Variant summary: NEB c.24094C>T (p.Arg8032X) 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 allele was found at a frequency of 0.00027 in 157874 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00027 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.24094C>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004551415	SCV004105496	likely pathogenic	NEB-related disorder	2023-08-24	criteria provided, single submitter	clinical testing	The NEB c.24094C>T variant is predicted to result in premature protein termination (p.Arg8032*). This variant was reported in an individual as part of a large genome-wide sequencing study and classified as likely pathogenic (Hou et al. 2020. PubMed ID: 31980526). This variant has also been reported with a second NEB variant in a pregnancy loss with fetal anomalies (Zhao et al. 2021. PubMed ID: 33100332). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152357937-G-A). Nonsense variants in NEB are expected to be pathogenic, and this variant has been classified as pathogenic or likely pathogenic by several independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/373977/). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003476003	SCV004200044	likely pathogenic	Arthrogryposis multiplex congenita 6	2023-10-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000576327	SCV000678085	uncertain significance	Nemaline myopathy 2	2019-06-20	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000416049	SCV001797593	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000416049	SCV001931214	likely pathogenic	not provided		no assertion criteria provided	clinical testing