ClinVar Miner

Submissions for variant NM_000286.3(PEX12):c.268_271del (p.Lys90fs) (rs61752100)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000595990 SCV000708096 pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000665252 SCV000789341 likely pathogenic Peroxisome biogenesis disorder type 3B; Peroxisome biogenesis disorder 3A 2017-01-26 criteria provided, single submitter clinical testing
Invitae RCV000690109 SCV000817787 pathogenic Peroxisome biogenesis disorder 3A 2020-08-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys90Glufs*3) in the PEX12 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs61752100, ExAC 0.02%). This variant has been observed in an individual affected with peroxisome-biogenesis disorder (PMID: 9792857). ClinVar contains an entry for this variant (Variation ID: 501646). Loss-of-function variants in PEX12 are known to be pathogenic (PMID: 9090384, 9632816, 21031596). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781708 SCV000919971 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2020-12-19 criteria provided, single submitter clinical testing Variant summary: PEX12 c.268_271delAAGA (p.Lys90GlufsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.4e-05 in 251150 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX12 causing Zellweger Syndrome (4.4e-05 vs 0.0016), allowing no conclusion about variant significance. c.268_271delAAGA has been reported in the literature in at-least one homozygous individual affected with Zellweger Syndrome and has been subsequently cited by others (example, Chang_1998, Ebberink_2011, Steinberg_2004, Moser_1999). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of PTS1 and PTS2 mediated protein import into the peroxisome (Chang_1998). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000595990 SCV001824666 pathogenic not provided 2019-08-07 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 15542397, 9792857, 21031596, 28492532, 10527683)

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