Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000128725 | SCV000517014 | pathogenic | not provided | 2015-05-26 | criteria provided, single submitter | clinical testing | The c.1204-1 G>A variant in the ZMPSTE24 gene has been reported previously in two compoundheterozygous siblings of Turkish ancestry diagnosed with mandibulo-acral dysplasia (Navarro et al., 2014). This splice site variant destroys the canonical splice acceptor site in intron 9. It is predicted to causeabnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1204-1G>A variant was not observed in approximately 6,500 individuals of European and African American ancestryin the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.We interpret c.1204-1 G>A as a pathogenic variant. |
Invitae | RCV000128725 | SCV004291788 | likely pathogenic | not provided | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 9 of the ZMPSTE24 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs61751009, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Mandibulo-acral dysplasia (PMID: 24169522). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140513). Variants that disrupt 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. 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. |
ZMPSTE24 homepage - |
RCV000128725 | SCV000172365 | not provided | not provided | no assertion provided | not provided |