Submissions for variant NM_001164508.2(NEB):c.24339_24342del (p.Pro8114fs)

dbSNP: rs934111355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641305	SCV000762946	pathogenic	Nemaline myopathy 2	2024-05-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro8149Serfs*30) 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 (no rsID available, gnomAD 0.001%). This premature translational stop signal has been observed in individuals with nemaline myopathy (PMID: 25205138, 26809617). This variant is also known as c.24339_24342del, p.Leu8113Leufs. ClinVar contains an entry for this variant (Variation ID: 533968). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000641305	SCV000789370	pathogenic	Nemaline myopathy 2	2017-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781650	SCV000919862	likely pathogenic	Nemaline myopathy	2023-04-03	criteria provided, single submitter	clinical testing	Variant summary: NEB c.24444_24447delACCT (p.Pro8149SerfsX30) 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 5e-06 in 200820 control chromosomes (gnomAD). c.24444_24447delACCT, which is located in an alternatively spliced exon (Lehtokari_2014), has been reported in the literature in the compound heterozygous state in two individuals affected with nemaline myopathy who had atypical and/or late onset of symptoms (Lehtokari_2014, Levesque_2016). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002507091	SCV002815197	pathogenic	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2024-03-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465401	SCV004200232	pathogenic	Arthrogryposis multiplex congenita 6	2023-06-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737920	SCV005361932	pathogenic	NEB-related disorder	2024-03-06	no assertion criteria provided	clinical testing	The NEB c.24444_24447delACCT variant is predicted to result in a frameshift and premature protein termination (p.Pro8149Serfs*30). Of note, this variant can also be referred to as c.24339_24342delACCT (p.Pro8114Serfs*30) with alternate isoform, NM_001164507. This variant has been reported in the compound heterozygous state in two individuals with nemaline myopathy (Lehtokari et al 2014. PubMed ID: 25205138; Reported as c.24339_24342del in Lévesque S et al 2016. PubMed ID: 26809617). This variant is reported in 0.0039% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in NEB are expected to be pathogenic. This variant is interpreted as pathogenic.