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

gnomAD frequency: 0.00010  dbSNP: rs187526749

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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 disorder	2022-06-29	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 (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. 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). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as VUS (n=2), Pathogenic (n=1) and likely 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 (Zellweger)	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 2 of the PEX12 gene. While this variant 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, gnomAD 0.05%). Disruption of this splice site 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). Variants that disrupt 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. 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.
Revvity Omics, Revvity	RCV000597979	SCV002021664	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004553310	SCV004121073	uncertain significance	PEX12-related disorder	2023-08-14	criteria provided, single submitter	clinical testing	The PEX12 c.681-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported without a second PEX12 variant in an individual with peroxisome biogenesis disorder (reported as IVS2-2A>C in Steinberg et al. 2004. PubMed ID: 15542397). This variant has also been reported along with two causative variants in the PEX6 gene in an individual with peroxisome biogenesis disorder (Yik et al. 2009. PubMed ID: 19105186). This variant is reported in 0.040% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org). Variants that disrupt consensus AG acceptor sites in PEX12 are expected to be pathogenic; however, this variant affects the final exon in PEX12 and therefore the transcript is not expected to undergo nonsense mediated decay. At this time, the clinical significance of this variant is uncertain.
Baylor Genetics	RCV000668976	SCV004201436	likely pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	2023-09-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000668976	SCV000793663	likely pathogenic	Peroxisome biogenesis disorder 3A (Zellweger)	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