The relationship between PEX19 and peroxisome biogenesis disorder (type 12A (Zellweger) included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of January, 2020. PEX19 encodes a peroxisome membrane protein involved in early peroxisome membrane biosynthesis prior to matrix protein import. Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis, involving at least 14 PEX genes. PEX19 belongs to complementation group J and mutations in the gene result in cells devoid of peroxisomal remnants (Waterham and Ebberink 2012, PMID 22871920) or with a small number of enlarged peroxisomes (Ebberink et al, 2010, PMID 20647552).
PEX19 was first reported in relation to autosomal recessive Peroxisome biogenesis disorder in 1999. (Matsuzono et al, PMID: 10051604). At least 3 nonsense or frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (12 points): Variants in this gene have been reported in at least 5 probands in 5 publications (PMID: 10051604, 20683989, 21031596, 30561787, 36931687). Variants in this gene segregated with 4 additional family members. The mechanism for disease is expected to be homozygous loss of function.
Summary of experimental data (4 points): This gene-disease association is supported by in vitro functional assays (PMIDs 21669930, 28526747, 12096124, 10051604). PEX19 interacts with PEX3, PEX11B and PEX16.
In summary, the PEX19-peroxisome biogenesis disorder gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Peroxisomal Disorders GCEP on January 17, 2020 (SOP Version 7). This gene-disease pair was originally evaluated by the Peroxisomal Disorders on January 17, 2020. It was reevaluated on April 27, 2023. As a result of this reevaluation, the classification did not change. The genetic evidence was updated and scored according SOP v9 and a new case report added, which maxed out the genetic evidence score.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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