ClinVar Miner

Submissions for variant NM_001127649.3(PEX26):c.230+1G>T

dbSNP: rs267608190
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001851574 SCV002228660 pathogenic Peroxisome biogenesis disorder 7A (Zellweger); Peroxisome biogenesis disorder 7B 2023-11-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Zellweger syndrome (PMID: 16257970, 27392320, 29947050). This variant is also known as intG231T. ClinVar contains an entry for this variant (Variation ID: 2159). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509142 SCV002819276 pathogenic Peroxisome biogenesis disorder 2022-12-05 criteria provided, single submitter clinical testing Variant summary: PEX26 c.230+1G>T 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: Four predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Furuki_2006). The variant was absent in 213784 control chromosomes. c.230+1G>T has been reported in the literature in individuals affected with Zellweger Syndrome (e.g. Weller_2005, Furuki_2006, Daum_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Weller_2005, Furuki_2006). The most pronounced variant effect results in <10% of normal activity, with the Pex26 variant protein showing only residual protein import function in peroxisomes and immunoblots showing complete absence of protein in human proband fibroblast skin lines (Weller_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000002242 SCV004201510 pathogenic Peroxisome biogenesis disorder 7A (Zellweger) 2023-03-17 criteria provided, single submitter clinical testing
OMIM RCV000002242 SCV000022400 pathogenic Peroxisome biogenesis disorder 7A (Zellweger) 2005-06-01 no assertion criteria provided literature only

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