ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665252 SCV000789341 likely pathogenic Infantile Refsum's disease; Peroxisome biogenesis disorder 3A 2017-01-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000595990 SCV000708096 pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781708 SCV000919971 likely pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-02-26 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 (e.g., p.Leu297fsX12). The variant allele was found at a frequency of 4.5e-05 in 246036 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PEX12 causing Zellweger Syndrome (4.5e-05 vs 0.0016), allowing no conclusion about variant significance. The c.268_271delAAGA variant has been reported in the literature in a homozygous individual affected with Zellweger Syndrome. These data indicate that the variant may be associated with disease. This publication reports experimental showing that this patient's fibroblasts have significantly reduced mRNA levels (34% of normal) and absent peroxisomal protein import (Chang_1998). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000690109 SCV000817787 pathogenic Peroxisome biogenesis disorder 3A 2018-06-05 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). 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.

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