ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781709 SCV000919972 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2021-04-16 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 prime acceptor site, one predict the variant strengthens a cryptic 3 prime acceptor site, one predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 248758 control chromosomes. 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. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Yik_2009). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS n=2, likely pathogenic/pathogenic n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000668976 SCV001419980 uncertain significance Peroxisome biogenesis disorder 3A 2019-11-05 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 2) of the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs187526749, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of peroxisome biogenesis disorder (PMID: 15542397, 19105186). ClinVar contains an entry for this variant (Variation ID: 497605). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000668976 SCV000793663 likely pathogenic Peroxisome biogenesis disorder 3A 2019-05-29 no assertion criteria provided clinical testing
New York Genome Center RCV000597979 SCV001431051 likely pathogenic not provided 2019-11-19 no assertion criteria provided clinical testing

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