Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001983443 | SCV002267997 | likely pathogenic | Fanconi anemia | 2022-10-13 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with SLX4-related conditions. This sequence change creates a premature translational stop signal (p.Gln1700Argfs*11) in the SLX4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 135 amino acid(s) of the SLX4 protein. This variant is present in population databases (no rsID available, gnomAD 0.007%). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the SLX1 interaction domain, which has been shown to be critical for SLX1-SLX4 complexing, and therefore will affect their Holliday junction resolvase and 5'-flap endonuclease activities (PMID: 19596235, 19596236). While functional studies have not been performed to directly test the effect of this variant on SLX4 protein function, this suggests that disruption of this region of the protein is causative of disease. 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. |