ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.1900+2T>C (rs1562857198)

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Total submissions: 3
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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 RCV000780587 SCV000917983 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-12-14 criteria provided, single submitter clinical testing Variant summary: PEX1 c.1900+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: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245962 control chromosomes. c.1900+2T>C has been reported in the literature in individuals affected with Zellweger Syndrome (Yik_PEX1_Hum Mutat_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic.
Invitae RCV001377624 SCV001575006 likely pathogenic Zellweger syndrome 2020-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 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 Zellweger spectrum disorder (PMID: 19105186). ClinVar contains an entry for this variant (Variation ID: 632940). 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, 26387595, 31831025). 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.
GeneDx RCV001570534 SCV001794839 pathogenic not provided 2021-01-11 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported in a patient with Zellweger syndrome who also harbored a frameshift variant in the PEX1 gene (Yik et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19105186, 25525159)

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