ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2926+1G>A (rs267608179)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169032 SCV000220182 likely pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2014-03-22 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000599041 SCV000340724 pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing
GeneDx RCV000599041 SCV000709922 likely pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The c.2926+1G>A variant in the PEX1 gene has been reported previously in association with Zellweger spectrum disorder (Reuber et al., 1997; Yik et al., 2009). This splice site variant destroys the canonical splice donor site in intron 18. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2926+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.2926+1G>A as a likely pathogenic variant.
Invitae RCV000169032 SCV000963840 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2018-12-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 of the PEX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs267608179, ExAC 0.004%). This variant has been observed in several individuals affected with Zellweger syndrome spectrum disorders (PMID: 19105186, 15542397, 21031596). ClinVar contains an entry for this variant (Variation ID: 188729). This variant has been reported to affect PEX1 protein function (PMID: 9398847). 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). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001194281 SCV001363681 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2019-10-18 criteria provided, single submitter clinical testing Variant summary: PEX1 c.2926+1G>A 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 that the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Reuber_1997). The variant allele was found at a frequency of 2e-05 in 251300 control chromosomes (gnomAD). c.2926+1G>A has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorder (e.g. Steinberg_2004, Reuber_1997, Yik_2009, Ebberink_2010) . These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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