Submissions for variant NM_001164508.2(NEB):c.6937C>T (p.Arg2313Ter)

gnomAD frequency: 0.00001  dbSNP: rs756363951

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV001797776	SCV005367884	pathogenic	Nemaline myopathy	2024-09-16	reviewed by expert panel	curation	The c.6937C>T (p.Arg2313Ter) variant in NEB is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 52/182 and to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v.4.1.0 is 0.00001669 (1/59924) in Admixed American which meets the threshold (MAF≤0.0000559) to apply PM2_Supporting. The variant was found in one proband with nemaline myopathy in the literature with a second nonsense variant identified in trans (PM3_Supporting, PMID: 25205138). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive nemaline myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PVS1, PM2_Supporting, PM3_Supporting (Congenital Myopathies VCEP specifications version 1; 09/16/2024)
Counsyl	RCV000667238	SCV000791658	likely pathogenic	Nemaline myopathy 2	2017-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797776	SCV002041627	likely pathogenic	Nemaline myopathy	2021-11-18	criteria provided, single submitter	clinical testing	Variant summary: NEB c.6937C>T (p.Arg2313X) 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 8.1e-06 in 247738 control chromosomes (gnomAD). c.6937C>T has been reported in the literature in a family affected with Nemaline Myopathy 2 (Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000667238	SCV002235700	pathogenic	Nemaline myopathy 2	2023-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552042). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). This variant is present in population databases (rs756363951, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg2313*) 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).
PreventionGenetics, part of Exact Sciences	RCV004547839	SCV004112528	pathogenic	NEB-related disorder	2023-02-27	criteria provided, single submitter	clinical testing	The NEB c.6937C>T variant is predicted to result in premature protein termination (p.Arg2313*). This variant was reported in the compound heterozygous state in an individual with nemaline myopathy (Lehtokari et al 2014. PubMed ID: 25205138). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-152507378-G-A). Nonsense variants in NEB are expected to be pathogenic. This variant is interpreted as pathogenic.