ClinVar Miner

Submissions for variant NM_000286.3(PEX12):c.681-2A>C (rs187526749)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668976 SCV000793663 likely pathogenic Infantile Refsum's disease; Peroxisome biogenesis disorder 3A 2017-08-22 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000597979 SCV000702219 pathogenic not provided 2016-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000597979 SCV000779656 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing The c.681-2A>C variant in the PEX12 gene has been reported previously in an individual with Zellweger spectrum disorder, however no second PEX12 variant was identified and this individual also harbored two variants in the PEX6 gene (Steinberg et al., 2004; Yik et al., 2009). This splice site variant destroys the canonical splice donor site in intron 2. 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.681-2A>C variant is observed in 25/243562 (0.01%) total alleles in large population cohorts (Lek et al., 2016). We interpret c.681-2A>C as a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781709 SCV000919972 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-05-23 criteria provided, single submitter clinical testing Variant summary: PEX12 c.681-2A>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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by RNA-splicing studies. A cell fusion complementation analysis showed that a Zellweger Syndrome patient had at least one functional PEX12 allele (Yik_2009). The variant allele was found at a frequency of 0.0001 in 243562 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PEX12 causing Zellweger Syndrome (0.0001 vs 0.0016), allowing no conclusion about variant significance. The variant, c.681-2A>C, has been reported in the literature in one individual affected with Zellweger Syndrome (Yik_2009) who also carried the PEX6 p.R601Q and p.R860Q alleles and was shown to lack PEX6 function. Authors considered all three PEX alleles to be inactivating. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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