ClinVar Miner

Submissions for variant NM_000286.3(PEX12):c.730_733dup (p.Leu245fs) (rs61752107)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409475 SCV000487601 pathogenic Infantile Refsum's disease 2016-08-16 criteria provided, single submitter clinical testing
Counsyl RCV000410995 SCV000487602 pathogenic Peroxisome biogenesis disorder 3A 2016-08-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728570 SCV000856162 pathogenic not provided 2018-04-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000410995 SCV000914758 pathogenic Peroxisome biogenesis disorder 3A 2017-09-05 criteria provided, single submitter clinical testing The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in a heterozygous state, all with peroxisome biogenesis disorders, with three specifically noted to be in the Zellweger syndrome spectrum (Chang et al. 1997; Steinberg et al. 2004; Yik et al. 2009; Ebberink et al. 2011). All individuals with the variant in a compound heterozygous state had a second insertion variant. Control data are unavailable for the p.Leu245CysfsTer19 variant, but it is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. To evaluate the effect of PEX12 expression on peroxisomal protein import, Chang et al. (1997) used patient fibroblasts and noted that when the variant was present, cDNA expression was observed in the cytoplasm only; however, expression of PEX12 in these cells reversed the effect and import into the peroxisomes was observed. Based on the evidence and due to the potential impact of frameshift variants, the p.Leu245CysfsTer19 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000781710 SCV000919973 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-08-02 criteria provided, single submitter clinical testing Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory, c.888_889delCT (p.Leu297fsX12). The variant allele was found at a frequency of 1.6e-05 in 244662 control chromosomes (gnomAD). The variant, c.730_733dupGCCT has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorders (Chang_1998, Cordoba_2018, Ebberink_2010,Yik_2009). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chang_1998). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000410995 SCV000950691 pathogenic Peroxisome biogenesis disorder 3A 2019-10-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PEX12 gene (p.Leu245Cysfs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acids of the PEX12 protein. This variant is present in population databases (rs61752107, ExAC 0.005%). This variant has been observed in several individuals affected with peroxisome biogenesis disorders (PMID: 9090384, 19105186). This variant is also known as c.733_734insGCCT in the literature. ClinVar contains an entry for this variant (Variation ID: 371737). Experimental studies have shown that this variant disrupts PEX12 expression (PMID: 9090384). This variant disrupts the C-terminus of the PEX12 protein. Other variant(s) that disrupt this region (p.Leu297Thrfs*12) have been determined to be pathogenic (PMID: 9792857, 25287621, 26094004, 14571262, 21031596). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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