ClinVar Miner

Submissions for variant NM_000318.3(PEX2):c.373C>T (p.Arg125Ter) (rs61752124)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664468 SCV000788430 likely pathogenic Peroxisome biogenesis disorder 5a (zellweger); Peroxisome biogenesis disorder 5B 2017-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780588 SCV000917985 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2018-06-04 criteria provided, single submitter clinical testing Variant summary: PEX2 c.373C>T (p.Arg125X) 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. The variant allele was found at a frequency of 8.2e-06 in 121346 control chromosomes. c.373C>T has been reported in the literature in individuals with biochemically confirmed Zellweger Syndrome . These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. 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 pathogenic.
Invitae RCV001053880 SCV001218163 pathogenic Peroxisome biogenesis disorder 5a (zellweger) 2019-04-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PEX2 gene (p.Arg125*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 181 amino acids of the PEX2 protein. This variant is present in population databases (rs61752124, ExAC 0.01%). This variant has been observed in individuals with Zellweger syndrome (PMID: 21465523, 9452066). ClinVar contains an entry for this variant (Variation ID: 549898). This variant has been reported to affect PEX2 protein function (PMID: 10528859). This variant disrupts the C-terminus of the PEX2 protein. Other variants that disrupt this region (p.Arg184Valfs*8, p.Trp223* p.Phe278Leufs*3, p.Ser289Lysfs*36) have been observed in individuals with PEX2-related conditions (PMID: 10652207, 14630978, 17041890). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.

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