Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002018562 | SCV002298922 | pathogenic | Peroxisome biogenesis disorder 7A (Zellweger); Peroxisome biogenesis disorder 7B | 2023-06-20 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with Zellweger syndrome (PMID: 15542397; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1514085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the PEX26 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509745 | SCV002819326 | likely pathogenic | Peroxisome biogenesis disorder | 2022-12-01 | criteria provided, single submitter | clinical testing | Variant summary: PEX26 c.667+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248876 control chromosomes (gnomAD). c.667+2T>C has been reported in the literature in an individual affected with features of Zellweger Syndrome (example: Steinberg_2004). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |