rs61750420

chr7-92501562-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:39 O:3
• 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]

ACMG classification

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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.2528G>A	p.Gly843Asp	missense_variant	15/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.2528G>A	p.Gly843Asp	missense_variant	15/24	1	NM_000466.3	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000322 AC: 81 AN: 251328 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000566 AC: 827 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.000556 AC XY: 404 AN XY: 727170

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000715

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74314

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000585 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:39 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:12

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PEX1: PM3:Very Strong, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
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, 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	- -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
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	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. -
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	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, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
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. -

Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:3 Other:1

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	Baylor Genetics	Dec 31, 2017	- -
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	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 14, 2022	ACMG codes:PS3; PS4; PM1; PM2; PM3_VS; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Peroxisome biogenesis disorder Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2012	- -
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. -
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. -

Zellweger spectrum disorders Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -

Peroxisome biogenesis disorder 1B Pathogenic:2

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	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. -

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 condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

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. -

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

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 15, 2019

- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.7	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.96
MVP		0.98
MPC		0.77
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61750420; hg19: chr7-92130876; COSMIC: COSV104373589; COSMIC: COSV104373589;