Submissions for variant NM_000318.3(PEX2):c.279_283del (p.Arg94fs)

dbSNP: rs61752122

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781714	SCV000919977	pathogenic	Peroxisome biogenesis disorder	2018-05-03	criteria provided, single submitter	clinical testing	Variant summary: PEX2 c.279_283delGAGAT (p.Arg94SerfsX5) 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. c.339_345delCAGGTGG (p.Arg114fsX1), c.355C>T (p.Arg119X)). The variant allele was found at a frequency of 1.6e-05 in 246158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PEX2 causing Zellweger Syndrome (1.6e-05 vs 0.0011), allowing no conclusion about variant significance. The variant, c.279_283delGAGAT, has been reported in the literature in at least two homozygous individuals and a compound heterozygous individual affected with Zellweger Syndrome (Gootjes 2004, Ebberink_2011). Gootjes et al. also reported experimental evidence evaluating an impact on protein function, demonstrating an absence of peroxisomes and severely decreased peroxisomal enzyme activities in patient fibroblasts. 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	RCV000128529	SCV001582806	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg94Serfs*5) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 212 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752122, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Zellweger syndrome spectrum (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 139588). This variant disrupts a region of the PEX2 protein in which other variant(s) (p.Arg184Valfs*8) have been determined to be pathogenic (PMID: 10652207; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000128529	SCV004201482	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2023-03-24	criteria provided, single submitter	clinical testing
OMIM	RCV000128529	SCV000172179	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2004-03-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001275875	SCV001461522	pathogenic	Zellweger spectrum disorders	2020-09-16	no assertion criteria provided	clinical testing