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

gnomAD frequency: 0.00001  dbSNP: rs61752124

Total submissions: 8

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780588	SCV000917985	pathogenic	Peroxisome biogenesis disorder	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)	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg125*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 181 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752124, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 9452066, 21465523). ClinVar contains an entry for this variant (Variation ID: 549898). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX2 function (PMID: 10528859). This variant disrupts the C-terminus of the PEX2 protein. Other variant(s) 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.
Fulgent Genetics, Fulgent Genetics	RCV000664468	SCV002811525	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger); Peroxisome biogenesis disorder 5B	2021-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003231574	SCV003930143	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	In vitro studies demonstrate the p.R125* variant has a deleterious effect on protein function with severely reduced PEX2 activity (Shimozawa et al., 1999); Nonsense variant predicted to result in protein truncation, as the last 181 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17045664, 11330042, 21465523, 9375798, Vo2021[abstract], Ranganath2022[abstract], 21031596, 9452066, 15542397, 10528859)
Baylor Genetics	RCV001053880	SCV004201463	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2023-10-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275871	SCV001461518	pathogenic	Zellweger spectrum disorders	2020-09-16	no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281578	SCV002570023	pathogenic	Peroxisome biogenesis disorder 5B	2002-09-08	no assertion criteria provided	research