Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000701148 | SCV000829932 | pathogenic | Nemaline myopathy 2 | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr7425*) 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 (rs748922882, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 12207938, 16917880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Tyr5689*. ClinVar contains an entry for this variant (Variation ID: 578209). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781648 | SCV000919859 | likely pathogenic | Nemaline myopathy | 2018-11-29 | criteria provided, single submitter | clinical testing | Variant summary: NEB c.22275C>G (p.Tyr7425X) 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 (eg. c.24407_24410dupTGTT (p.Leu8137fsX18), c.24559C>T (p.Arg8187X), and c.24632_24633delCT (p.Pro8211fsX4)). The variant allele was found at a frequency of 8.1e-06 in 245950 control chromosomes (gnomAD). The variant, c.22275C>G, has been reported in the literature in an individual affected with Nemaline Myopathy 2 (Pelin_2002). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV002499258 | SCV002811672 | pathogenic | Nemaline myopathy 2; Arthrogryposis multiplex congenita 6 | 2022-02-03 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000701148 | SCV003761409 | pathogenic | Nemaline myopathy 2 | 2023-01-25 | criteria provided, single submitter | curation | The heterozygous p.Tyr7425Ter variant in NEB was identified, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 1458230), in one individual with nemaline myopathy. This individual also carried a likely pathogenic variant (ClinVar Variation ID: 1458230), however, the phase of these variants are unknown at this time. The p.Tyr7425Ter variant in NEB has been previously reported in 4 unrelated individuals with nemaline myopathy (PMID: 36233295, PMID: 16917880, PMID: 12207938, PMID: 25205138) but has been identified in 0.006% (2/34488) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748922882). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 unrelated individuals, 3 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 16917880, PMID: 25205138, ClinVar Variation ID: 1458230; PMID: 36233295, ClinVar Variation ID: 521691), which increases the likelihood that the p.Tyr7425Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 578209) and has been interpreted as pathogenic by Fulgent Genetics and Invitae and as likely pathogenic by Women's Health and Genetics/Laboratory Corporation of America, LabCorp. This nonsense variant leads to a premature termination codon at position 7425, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy 2. In summary, this variant meets criteria to be classified as pathogenic for nemaline myopathy 2. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015). |
| Baylor Genetics | RCV003465616 | SCV004200050 | pathogenic | Arthrogryposis multiplex congenita 6 | 2023-10-26 | criteria provided, single submitter | clinical testing |