Submissions for variant NM_000318.3(PEX2):c.355C>T (p.Arg119Ter)

gnomAD frequency: 0.00006  dbSNP: rs61752123

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589554	SCV000696558	pathogenic	Peroxisome biogenesis disorder	2017-03-31	criteria provided, single submitter	clinical testing	Variant summary: The PEX2 c.355C>T (p.Arg119X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0002708 (34/125548 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX2 variant (0.001118). Several publications have cited the variant in patients with diagnoses that are confirmed with standard biochemical tests. Additionally, a functional study demonstrated a lack of peroxisome formation via immunofluorescence in cultured fibroblasts of a patient who was homozygous for the variant of interest (Imamura_AJHG_1998). Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014703	SCV000949919	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2024-10-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg119*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752123, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorders (PMID: 1546315, 7681622, 9452066, 9585609, 10528859, 15542397, 21465523, 23430938). ClinVar contains an entry for this variant (Variation ID: 13704). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000014703	SCV001194007	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2019-12-26	criteria provided, single submitter	clinical testing	NM_000318.2(PEX2):c.355C>T(R119*) is classified as pathogenic in the context of peroxisome biogenesis disorder type 5. Sources cited for classification include the following: PMID 15542397, 1546315 and 14630978. Classification of NM_000318.2(PEX2):c.355C>T(R119*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
AiLife Diagnostics, AiLife Diagnostics	RCV002223176	SCV002501450	pathogenic	not provided	2021-06-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496363	SCV002811101	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger); Peroxisome biogenesis disorder 5B	2024-04-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014703	SCV004201464	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002223176	SCV004237810	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing
OMIM	RCV000014703	SCV000034958	pathogenic	Peroxisome biogenesis disorder 5A (Zellweger)	2014-04-01	no assertion criteria provided	literature only
OMIM	RCV000032924	SCV000056696	pathogenic	Peroxisome biogenesis disorder 5B	2014-04-01	no assertion criteria provided	literature only
Counsyl	RCV000032924	SCV000487550	pathogenic	Peroxisome biogenesis disorder 5B	2016-08-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001275872	SCV001461519	pathogenic	Zellweger spectrum disorders	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748521	SCV005360603	pathogenic	PEX2-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The PEX2 c.355C>T variant is predicted to result in premature protein termination (p.Arg119*). This variant has been reported in the homozygous and compound heterozygous states in several individuals with Zellweger syndrome (Steinberg et al. 2004. PubMed ID: 15542397; Ebberink et al. 2011. PubMed ID: 21031596; Shimozawa et al. 1999. PubMed: 10528859). This variant is reported in 0.24% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in PEX2 are expected to be pathogenic. This variant is interpreted as pathogenic.