Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000671466 | SCV000796442 | uncertain significance | Nemaline myopathy 2 | 2017-12-14 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000671466 | SCV000816770 | pathogenic | Nemaline myopathy 2 | 2018-10-02 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 23 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in 2 siblings affected with nemaline myopathy, the variant also segregated with disease in this family (PMID: 21724397). This variant has also been observed in combination with another NEB variant in an individual affected with nemaline myopathy (Invitae). These findings are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has been reported in individuals in the Universal Mutation Database Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 555613). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. |