Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000684902 | SCV000812363 | likely pathogenic | Cornelia de Lange syndrome 1 | 2018-08-07 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 43 of the NIPBL gene. It does not directly change the encoded amino acid sequence of the NIPBL 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 reported to segregate with disease in a family affected with Cornelia de Lange Syndrome (PMID: 15318302) and has also been reported in an additional, unrelated, affected individual (PMID: 17661813). This variant is also known as c.7321+4A>G in the literature. 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 is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV002289957 | SCV002578607 | pathogenic | not provided | 2022-04-05 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that this variant causes abnormal splicing with skipping of exon 43 in a subset of transcripts (Aoi et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31337854, 17661813, 15318302) |