Submissions for variant NM_000466.3(PEX1):c.2528G>A (p.Gly843Asp)

gnomAD frequency: 0.00025  dbSNP: rs61750420

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078922	SCV000281262	pathogenic	not provided	2015-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000078922	SCV000329458	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Published functional studies using a mouse model of G843D (in mice G844D) demonstrate PEX1-G844D homozygous mice recapitulate many classic features of mild ZSD cases, including growth retardation and fatty livers with cholestasis (Hiebler et al., 2014); This variant is associated with the following publications: (PMID: 22871920, 17055079, 21862673, 16141001, 11389485, 25412400, 12402331, 26219880, 27872819, 31150129, 30577886, 31980526, 31216405, 27090541, 26643206, 27882258, 29766340, 21846392, 21031596, 15098231, 10384394, 9398848, 29377746, 29419819, 29287774, 28857144, 29247835, 10447258, 26303611, 29588463, 28559085, 29907799, 31664448, 32866347, 34426522, 31589614, 31884617, 31319225, 9398847, 26287655, 33869228, 34434934, 34703844, 24503136)
Eurofins Ntd Llc (ga)	RCV000078922	SCV000331469	pathogenic	not provided	2016-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000032927	SCV000470509	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2017-04-27	criteria provided, single submitter	clinical testing	The PEX1 c.2528G>A (p.Gly843Asp) missense variant has been reported in two studies in which it was found in a total of 33 patients with Zellweger syndrome, including in 12 patients in a homozygous state, six patients in a compound heterozygous state, and 15 patients in a heterozygous state (Reuber et al. 1997; Thoms et al. 2011). The p.Gly843Asp variant was present in a heterozygous state in one of 78 controls and is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. This variant is conserved between human and yeast. The p.Gly843Asp variant protein, when transfected into fibroblasts derived from a patient diagnosed with peroxisomal biogenesis disorder, failed to mediate PAHXmyc import in most cells and showed about 15% activity when compared to the wild type assay. Some genotype-phenotype correlation was noted, with five of six homozygotes for the p.Gly843Asp variant diagnosed with infantile Refsum disease or neonatal adrenoleukodystrophy, which are considered to be more mild phenotypes in the Zellweger spectrum. Based on the collective evidence, the p.Gly843Asp) variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007946	SCV000696782	pathogenic	Peroxisome biogenesis disorder	2022-05-19	criteria provided, single submitter	clinical testing	Variant summary: PEX1 c.2528G>A (p.Gly843Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251472 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PEX1 causing Zellweger Syndrome (0.00033 vs 0.0039), allowing no conclusion about variant significance. The variant has been observed in many ZS patients reported in the literature in both compound heterozygous and homozygous states. 19 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.
Invitae	RCV001376560	SCV000754533	pathogenic	Zellweger spectrum disorders	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 843 of the PEX1 protein (p.Gly843Asp). This variant is present in population databases (rs61750420, gnomAD 0.06%). This missense change has been observed in individual(s) with peroxisomal biogenesis disorder (PMID: 9398847, 10447258, 26287655, 26643206, 27090541, 27872819, 27882258). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7516). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PEX1 function (PMID: 12402331, 24503136). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000032927	SCV000784275	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000345695	SCV000784276	pathogenic	Peroxisome biogenesis disorder 1B	2018-03-05	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000661947	SCV000784277	pathogenic	Heimler syndrome 1	2018-03-05	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000032927	SCV000803535	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic, for Peroxisome biogenesis disorder 1A (Zellweger), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Most common mutation found in multiple unrelated patients (PMID:9398847,11389485,19105186,16141001). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:9398847). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:15098231).
Fulgent Genetics, Fulgent Genetics	RCV000763596	SCV000894441	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B	2018-10-31	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000791271	SCV000930557	pathogenic	Peroxisomal disorder	2018-03-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763596	SCV000992800	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B	2017-12-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004322	SCV001163203	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000032927	SCV001193911	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2019-10-18	criteria provided, single submitter	clinical testing	NM_000466.2(PEX1):c.2528G>A(G843D) is classified as pathogenic in the context of peroxisome biogenesis disorder type 1. Sources cited for classification include the following: PMID 21031596, 16141001, 12402331, 9398848, 15098231, 9398847, 10384394. Classification of NM_000466.2(PEX1):c.2528G>A(G843D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Myriad Genetics, Inc.	RCV000345695	SCV001193912	pathogenic	Peroxisome biogenesis disorder 1B	2019-10-18	criteria provided, single submitter	clinical testing	NM_000466.2(PEX1):c.2528G>A(G843D) is classified as pathogenic in the context of peroxisome biogenesis disorder type 1. Sources cited for classification include the following: PMID 21031596, 16141001, 12402331, 9398848, 15098231, 9398847, 10384394. Classification of NM_000466.2(PEX1):c.2528G>A(G843D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics	RCV001074120	SCV001239689	pathogenic	Retinal dystrophy	2019-01-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078922	SCV001246665	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PEX1: PM3:Very Strong, PM2
Elsea Laboratory, Baylor College of Medicine	RCV001004322	SCV001424249	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B	2020-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266794	SCV001444973	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000078922	SCV001468913	pathogenic	not provided		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000661947	SCV001530405	pathogenic	Heimler syndrome 1	2018-03-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731280	SCV001984005	pathogenic	not specified	2020-07-21	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000661947	SCV002762729	pathogenic	Heimler syndrome 1	2022-10-14	criteria provided, single submitter	research	ACMG codes:PS3; PS4; PM1; PM2; PM3_VS; PP3
Athena Diagnostics Inc	RCV000078922	SCV002817195	pathogenic	not provided	2021-09-03	criteria provided, single submitter	clinical testing	Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 9398847, 24503136). This variant has been identified as homozygous or compound heterozygous in multiple individuals with clinical features associated with this gene and appears to segregate with disease in at least one family (PMID: 26643206, 31374812, 27882258, 27872819, 26287655, 30577886, 11389485, 9398847, 9398848, 16141001, 12032265, 27090541). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Revvity Omics, Revvity	RCV000078922	SCV003824854	pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000032927	SCV003839138	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2022-11-22	criteria provided, single submitter	clinical testing	c.2528G>A in PEX1 has been reported in multiple individuals affected with Zellweger spectrum disorder and has been shown to result in reduced PEX1 protein activity. This variant (rs61750420) has been reported in ClinVar (Variation ID 7516), and is rare (<0.1%) in a large population dataset (gnomAD: 89/282722 total alleles; 0.0315%; no homozygotes). We consider c.2528G>A; p.Gly843Asp in PEX1 to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398462	SCV004104441	pathogenic	PEX1-related condition	2023-12-15	criteria provided, single submitter	clinical testing	The PEX1 c.2528G>A variant is predicted to result in the amino acid substitution p.Gly843Asp. This variant has been reported as a common pathogenic variant associated with autosomal recessive peroxisome biogenesis disorders (PBD) (Rosewich et al. 2005. PubMed ID: 16141001; Imamura et al. 1998. PubMed ID: 9817926; Gärtner et al. 1999. PubMed ID: 10384394; https://www.ncbi.nlm.nih.gov/books/NBK1448/). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7516). Taken together, this variant is interpreted as pathogenic.
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000763596	SCV004239259	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B	2023-09-15	criteria provided, single submitter	clinical testing
OMIM	RCV000007946	SCV000028151	pathogenic	Peroxisome biogenesis disorder	2012-09-01	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000022416	SCV000043702	not provided	Leber congenital amaurosis	2013-01-22	no assertion provided	curation
OMIM	RCV000032927	SCV000056699	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2012-09-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000032927	SCV000238461	pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)	2014-07-31	no assertion criteria provided	research	The variant (c.2528G>A; p.Gly843Asp) has been reported in individuals with peroxisome biogenesis disorders (Reuber et al. 1997 PMID: 9398847; Portsteffen et al. 1997 PMID: 9398848; Rosewich et al. 2005 PMID: 16141001). This variant is the most common variant associated with Zellweger syndrome. Computational evidence and results from functional studies support the pathogenicity of this variant (Reuber et al., 1997 PMID: 9398847; Portsteffen et al. 1997 PMID: 9398848; Geisbrecht et al. 1998; Imamura et al. 1998; Walter et al. 2001 PMID: 11389485; Tamura et al. 2001; Rosewich et al. 2005).
Mayo Clinic Laboratories, Mayo Clinic	RCV000078922	SCV000801848	pathogenic	not provided	2017-07-13	no assertion criteria provided	clinical testing
GeneReviews	RCV000007946	SCV001478320	not provided	Peroxisome biogenesis disorder		no assertion provided	literature only	NM_000466.2:c.2528G>A and NM_000466.2:c.2097dupT are the most common PEX1 variants; about 80% of persons with a PEX1 pathogenic variant have at least 1 of these common alleles.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078922	SCV001744345	pathogenic	not provided		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000032927	SCV001760198	likely pathogenic	Peroxisome biogenesis disorder 1A (Zellweger)		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078922	SCV001927709	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078922	SCV001959930	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078922	SCV001970240	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000763596	SCV002074879	not provided	Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV001376560	SCV002076859	pathogenic	Zellweger spectrum disorders	2017-03-17	no assertion criteria provided	clinical testing