Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Institute Rare Disease Group, |
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). |
| Invitae | RCV001004942 | SCV001225725 | pathogenic | Nemaline myopathy 2 | 2019-09-09 | 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. This variant has not been reported in the literature in individuals with NEB-related conditions. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic. |