ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.1239+1G>T

gnomAD frequency: 0.00002  dbSNP: rs756876301
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376605 SCV000754535 pathogenic Zellweger spectrum disorders 2024-01-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the PEX1 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 PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs756876301, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with peroxisomal biogenesis disorder (PMID: 19105186, 26387595). ClinVar contains an entry for this variant (Variation ID: 217430). 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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000633316 SCV000890871 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2017-11-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004518 SCV001163563 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B criteria provided, single submitter clinical testing
Baylor Genetics RCV000633316 SCV001524805 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2020-01-31 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526999 SCV001737802 pathogenic Peroxisome biogenesis disorder 2021-05-19 criteria provided, single submitter clinical testing Variant summary: PEX1 c.1239+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: Three 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 1.6e-05 in 251132 control chromosomes (gnomAD). c.1239+1G>T has been reported in the literature in individuals affected with Zellweger Syndrome Spectrum disorders (e.g. Yik_2009, Ebberink_2011, Ratbi_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001795328 SCV002032659 pathogenic not provided 2021-12-03 criteria provided, single submitter clinical testing Identified with a frameshift variant in an individual suspected of having a peroxisomal biogenesis disorder (Yik et al., 2009); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26387595, 19105186)
PreventionGenetics, part of Exact Sciences RCV003422106 SCV004117013 pathogenic PEX1-related condition 2022-09-06 criteria provided, single submitter clinical testing The PEX1 c.1239+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in multiple patients with peroxisomal biogenesis disorders, including Zellweger syndrome and Heimler syndrome (referred to as c.1240+1G>T in Yik et al. 2009. PubMed ID: 19105186; Ebberink et al. 2011. PubMed ID: 21031596; Ratbi et al. 2015. PubMed ID: 26387595; Gao et al. 2019. PubMed ID: 31831025). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-92146589-C-A). Variants that disrupt the consensus splice donor site in PEX1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV000201308 SCV004203264 pathogenic Heimler syndrome 1 2023-10-20 criteria provided, single submitter clinical testing
OMIM RCV000201308 SCV000256091 pathogenic Heimler syndrome 1 2015-10-01 no assertion criteria provided literature only
Natera, Inc. RCV001376605 SCV002076916 pathogenic Zellweger spectrum disorders 2020-09-12 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.