ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2071+1G>T

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193609 SCV001362557 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-05-31 criteria provided, single submitter clinical testing Variant summary: PEX1 c.2071+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: 4/5 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250890 control chromosomes. c.2071+1G>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Walter_2001, Ebberink_2010, Berendse_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating a reduction in PEX1 protein expression in fibroblasts cultured from an individual with this variant (Walter_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001377623 SCV001575005 likely pathogenic Zellweger syndrome 2020-03-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the PEX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with infantile Refsum disease (PMID: 11389485). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). 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.

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