Submissions for variant NM_000466.3(PEX1):c.2614C>T (p.Arg872Ter)

gnomAD frequency: 0.00001  dbSNP: rs61750422

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254886	SCV000322246	pathogenic	not provided	2024-03-06	criteria provided, single submitter	clinical testing	Has been reported previously in individuals with PEX1-related disorders (PMID: 12032265, 16141001, 19105186, 21846392); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19105186, 21846392, 16141001, 12032265, 31964843)
Baylor Genetics	RCV001004321	SCV001163202	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376587	SCV001228755	pathogenic	Zellweger spectrum disorders	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg872*) in the PEX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 21031596, 26387595, 31831025). This variant is present in population databases (rs61750422, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with PEX1-related conditions (PMID: 12032265, 19105186, 21846392). ClinVar contains an entry for this variant (Variation ID: 265395). For these reasons, this variant has been classified as Pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001063888	SCV001251518	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)		criteria provided, single submitter	research	The PEX1 c.2614C>T (p.R872*) nonsense variant is predicted to result in an aberrant or absent protein. This variant has been reported in the homozygous and compound heterozygous state in individuals with Zellweger spectrum disorder (PMID: 21031596; 12032265; 19105186; 20301621).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260325	SCV001437250	pathogenic	Peroxisome biogenesis disorder	2020-09-21	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.2614C>T (p.Arg872X) 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. The variant allele was found at a frequency of 1.2e-05 in 251050 control chromosomes. c.2614C>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome with elevated VCLFA (very long chain fatty acid) levels (example, Preuss_2002, Yik_2009, Thoms_2011, Alshenaifi_2019). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814132	SCV001755364	pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252071	SCV002522989	pathogenic	See cases	2022-01-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2
Revvity Omics, Revvity	RCV000254886	SCV003824832	pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475860	SCV004203283	pathogenic	Heimler syndrome 1	2023-09-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001063888	SCV004801178	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2024-03-14	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001063888	SCV005087041	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Heimler syndrome 1 (MIM#234580), peroxisome biogenesis disorder 1A (Zellweger; MIM#214100) and peroxisome biogenesis disorder 1B (NALD/IRD; MIM#601539). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Zellweger spectrum disorder and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 19105186). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001376587	SCV002076853	pathogenic	Zellweger spectrum disorders	2017-03-17	no assertion criteria provided	clinical testing