Submissions for variant NM_001164508.2(NEB):c.13147C>T (p.Gln4383Ter)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004942	SCV001164465	likely pathogenic	Nemaline myopathy 2	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Gln4383Ter variant in NEB was identified by our study in the compound heterozygous state, with a VUS, in one individual with nemaline myopathy. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 4383, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish clinical significance, the p.Gln4383Ter variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001004942	SCV001225725	pathogenic	Nemaline myopathy 2	2024-03-02	criteria provided, single submitter	clinical testing	This variant occurs in a region of NEB (Exons 82-105) consisting of three highly homologous 8-exon repeat units (exons 82-89, exons 90-97, exons 98-105). Sequence variants in this region can be detected, but this assay cannot determine which of the three repeat units is affected, and zygosity is often ambiguous. All variants in this region are reported relative to the exon 82-89 repeat. This sequence change creates a premature translational stop signal (p.Gln4383*) 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). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with clinical features of NEB-related conditions (PMID: 33442022). ClinVar contains an entry for this variant (Variation ID: 813958). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004553551	SCV004117909	pathogenic	NEB-related disorder	2023-10-10	criteria provided, single submitter	clinical testing	The NEB c.13147C>T variant is predicted to result in premature protein termination (p.Gln4383*). This variant was reported in the compound heterozygous state in an individual with nemaline myopathy 2 (Tolusso et al 2021. PubMed ID: 33442022). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in NEB are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003467576	SCV004200090	pathogenic	Arthrogryposis multiplex congenita 6	2024-02-16	criteria provided, single submitter	clinical testing

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