ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.1962-1G>A (rs267608229)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665084 SCV000789145 pathogenic Peroxisome biogenesis disorder 4a (zellweger); Peroxisome biogenesis disorder 4B 2017-01-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280661 SCV001467950 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2020-12-14 criteria provided, single submitter clinical testing Variant summary: PEX6 c.1962-1G>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: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251450 control chromosomes (gnomAD). c.1962-1G>A has been reported in the literature in individuals affected with Zellweger Syndrome and Peroxisome biogenesis disorders (Yahraus_1996, Yik_2009, Ebberink_2010). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Yahraus_1996, Weller_2005). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV001280661 SCV001579764 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2020-02-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the PEX6 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 peroxisome biogenesis disorders (PMID:8670792, 19105186). ClinVar contains an entry for this variant (Variation ID: 550358). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8670792). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PEX6 are known to be pathogenic (PMID: 8670792, 19877282, 21031596). For these reasons, this variant has been classified as Pathogenic.

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