ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2528G>A (p.Gly843Asp) (rs61750420)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000763596 SCV000992800 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Deafness enamel hypoplasia nail defects; Peroxisome biogenesis disorder 1B 2017-12-31 criteria provided, single submitter clinical testing
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
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000022416 SCV000043702 not provided Leber congenital amaurosis 2013-01-22 no assertion provided curation
Counsyl RCV000032927 SCV000678082 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2015-07-21 criteria provided, single submitter clinical testing
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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078922 SCV000331469 pathogenic not provided 2016-01-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763596 SCV000894441 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Deafness enamel hypoplasia nail defects; Peroxisome biogenesis disorder 1B 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000078922 SCV000329458 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The G843D variant in the PEX1 gene has been reported previously as a common pathogenic variant in peroxisome biogenesis disorders when present in affected individuals in the homozygous state or in trans with another disease-causing variant (Reuber et al., 1997; Collins et al., 1999; Berendse et al., 2016). The G843D variant has also been observed multiple times in trans with a pathogenic allele in unrelated patients referred for genetic testing at GeneDx. This variant is observed in 79/126590 alleles (0.062%) from individuals of non-Finnish European background, and 87/277072 total alleles in large population cohorts (Lek et al., 2016). The G843D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies in a patient-derived cell line suggest that the G843D variant has reduced ability to import proteins as compared to wild type (Reuber et al., 1997). We interpret G843D as a pathogenic variant.
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 Deafness enamel hypoplasia nail defects 2018-03-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America RCV000007946 SCV000696782 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The PEX1 c.2528G>A (p.Gly843Asp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 32/121394 control chromosomes at a frequency of 0.0002636, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873). The variant has been observed in many ZS patients reported in the literature in both compound heterozygous and homozygous states. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000032927 SCV000754533 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 843 of the PEX1 protein (p.Gly843Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs61750420, ExAC 0.04%). This variant has been reported as homozygous or in combination with another PEX1 variant, which is a known pathogenic variant in some instances, in many individuals affected with a peroxisomal biogenesis disorder (PMID: 10447258, 27882258, 27090541, 27872819, 26643206, 9398847, 26287655). It has been also observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with Zellweger syndrome (PMID:27090541). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 7516). Experimental studies have shown that this missense change disrupts peroxisomal protein import (PMID: 12402331, 24503136). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000078922 SCV000801848 pathogenic not provided 2017-07-13 no assertion criteria provided clinical testing
OMIM RCV000007946 SCV000028151 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 2012-09-01 no assertion criteria provided literature only
OMIM RCV000032927 SCV000056699 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2012-09-01 no assertion criteria provided literature only
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).
Undiagnosed Diseases Network,NIH RCV000791271 SCV000930557 pathogenic Peroxisomal disorder 2018-03-16 criteria provided, single submitter clinical testing

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