rs61750420
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000466.3(PEX1):c.2528G>A(p.Gly843Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00057 ( 0 hom. )
Consequence
PEX1
NM_000466.3 missense
NM_000466.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.54
Genes affected
PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
Variant 7-92501562-C-T is Pathogenic according to our data. Variant chr7-92501562-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92501562-C-T is described in Lovd as [Pathogenic]. Variant chr7-92501562-C-T is described in Lovd as [Pathogenic]. Variant chr7-92501562-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000335 AC: 51AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000322 AC: 81AN: 251328Hom.: 0 AF XY: 0.000317 AC XY: 43AN XY: 135826
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GnomAD4 exome AF: 0.000566 AC: 827AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.000556 AC XY: 404AN XY: 727170
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GnomAD4 genome 0.000335 AC: 51AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74314
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:43Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:12
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 26, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 23, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratoire de Génétique Moléculaire, CHU Bordeaux | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 06, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 05, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 03, 2021 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | PEX1: PM3:Very Strong, PM2 - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2012 | - - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 31, 2014 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | 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). - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostics Centre, Carl Von Ossietzky University Oldenburg | Nov 15, 2023 | The variant PEX1:c.2528G>A, p.(Gly843Asp), which is located in the coding exon 15 of the PEX1 gene, results from a guanine to adenosine substitution at nucleotide position c.2528. The glycine at protein position 843 is replaced by an asparagine, an amino acid with modified properties. The amino acid position is highly conserved in evolutionary terms. In addition, in silico tools predict a severe deleterious effect in the protein structure/function (REVEL = 0.98). The variant is classified as rare in the overall population (allele frequency= 0.0005440 in gnomAD, v4.1.0). The variant has been consistently described as Pathogenic or Likely pathogenic in 42 entries in ClinVar (ClinVar ID: 7516). The variant has been described in multiple publications in homozygous and compound heterozygous state in patients with peroxisomal diseases and represents one of the most frequent pathogenic alterations in Zellweger syndrome (PMID: 9398847, 10447258, 15098231, 16141001). In homozygous state, this alteration often leads to a milder course of the disease than truncating PEX1 alterations (PMID:15098231). Functional studies conducted in a mouse model demonstrated a deleterious effect in protein function and recapitulate the human phenotype (PMID: 22871920, 24503136). In summary, the variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Nov 22, 2022 | 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. - |
Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2017 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Sep 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Heimler syndrome 1 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 14, 2022 | ACMG codes:PS3; PS4; PM1; PM2; PM3_VS; PP3 - |
Peroxisome biogenesis disorder Pathogenic:2Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 19, 2022 | 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. - |
| not provided, no classification provided | literature only | GeneReviews | - | 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. - |
Zellweger spectrum disorders Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2025 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PEX1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PEX1 function (PMID: 12402331, 24503136). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Peroxisome biogenesis disorder 1B Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 18, 2019 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Retinal dystrophy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 15, 2019 | - - |
Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Elsea Laboratory, Baylor College of Medicine | Apr 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2014 | - - |
PEX1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 11, 2024 | 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). 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. - |
Peroxisome biogenesis disorder due to PEX1 defect Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | 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) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (89 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported greater than thirty times as pathogenic in ClinVar. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000466.2:c.2528G>A; p.(Gly973Alafs*16)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jul 21, 2020 | - - |
Peroxisomal disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 16, 2018 | - - |
Leber congenital amaurosis Other:1
| not provided, no classification provided | curation | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jan 22, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MVP
MPC
0.77
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at