rs61750415

Variant names:

• chr7-92503169-T-TA
• rs61750415
• NM_000466.3:c.2097dupT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000466.3(PEX1):​c.2097dupT​(p.Ile700TyrfsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: PEX1 NM_000466.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:40 O:1
• Conservation: PhyloP100: -0.157
• Publications: 35 publications found

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]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, Ambry Genetics
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-92503169-T-TA is Pathogenic according to our data. Variant chr7-92503169-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 7519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.2097dupT	p.Ile700TyrfsTer42	frameshift_variant	Exon 13 of 24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.2097dupT	p.Ile700TyrfsTer42	frameshift_variant	Exon 13 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000502 AC: 126 AN: 251142 AF XY: 0.000508

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000986

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000809 AC: 1183 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.000787 AC XY: 572 AN XY: 727036

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.000224 AC: 10 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00102 AC: 1129 AN: 1111754

Other (OTH) AF: 0.000414 AC: 25 AN: 60380

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74478

African (AFR) AF: 0.000217 AC: 9 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000628 Hom.: 0

Bravo AF: 0.000589

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:40 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:13

Jun 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Complementation studies found that this variant results in no functional complementation while control PEX1 cDNA rescued the impaired peroxisome biogenesis in patient cells (Ratbi et al., 2015); Frameshift 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; This variant is associated with the following publications: (PMID: 28468868, 30266093, 29419819, 10447258, 20952722, 26387595, 12402331, 26643206, 26287655, 29377746, 29431110, 29261186, 30487145, 31150129, 31831025, 31054281, 30577886, 32627857, 32866347, 31980526, 31216405, 31589614, 31884617, 20301621) -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PEX1: PM3:Very Strong, PVS1, PM2 -

Mar 30, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. 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: 20952722, 31150129, 29377746, 30577886, 16141001, 15542397, 12032265, 11389485, 10480353, 28468868, 26387595, 26287655, 26643206, 10447258). 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. -

May 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PS4_moderate -

Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:7

Oct 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 15, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant PEX1:c.2097dupT, p.(Ile700Tyrfs*42), which is located in the coding exon 13 of the PEX1 gene, results from a single-base insertion at nucleotide position c.2097. The variant causes a frameshift that results in the replace of an isoleucine by a tyrosine at protein position 700, followed by a premature translation stop codon after 42 amino acids. The variant affects an exon (13/24) present in a biologically relevant transcript and is predicted to cause protein truncation/absent due to nonsense mediated decay in a gene where loss-of-function is a known mechanism of disease. The variant has been consistently described as Pathogenic or Likely pathogenic in 37 entries in ClinVar (ClinVar ID: 7519). 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 changes in Zellweger syndrome (PMID: 10447258, 15098231, 16141001). The variant is classified as rare in the overall population (allele frequency= 0.0007808 in gnomAD, v4.1.0). In summary, this variant is classified as Pathogenic. -

Sep 20, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS3, PM2 -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000466.2(PEX1):c.2097dupT(aka I700Yfs*42) is classified as pathogenic in the context of peroxisome biogenesis disorder type 1. Sources cited for classification include the following: PMID 12402331, 15098231, 20952722, 21031596, 10447258 and 16141001. Classification of NM_000466.2(PEX1):c.2097dupT(aka I700Yfs*42) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -

Nov 22, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.2097dupT in PEX1 has been reported in multiple individuals affected with Zellweger spectrum disorder. This variant (rs61750415) has been reported in ClinVar (variation ID 7519), and is rare (<0.1%) in a large population dataset (gnomAD: 137/282532 total alleles; 0.0485%; no homozygotes). This frameshift variant results in a premature stop codon in exon 13 of 24, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider c.2097dupT;p.Ile700fs in PEX1 to be pathogenic. -

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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PEX1 c.2097dupT [p.I700fs] is a pathogenic frameshift variant predicted to result in premature truncation or absence of the PEX1 protein and resulting in PEX1 loss of function (PMID: 10447258). This is a rare variant that has been previously reported in Zellweger spectrum disorder (PMID:10447258; 10480353; 11389485; 12032265; 15542397; 16141001; 26387595). -

Jul 27, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Heimler syndrome 1 Pathogenic:3

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1B Pathogenic:3

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. This variant was detected in homozygous state. -

Aug 28, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant in exon 13 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a homozygous or compound heterozygous change in multiple patients with Zellweger spectrum disorders (PMID: 10447258). This variant is commonly observed in affected individuals with an estimated allele frequency of 0.35 among PEX1-deficient patients (PMID: 17055079). Functional studies confirm this variant results in decreased mRNA levels and loss of protein function (PMID: 10447258). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.05 % (139/276872) and thus is presumed to be rare. Based on the available evidence, the c.2097dupT (p.Ile700TyrfsTer42) variant is classified as pathogenic. -

Sep 07, 2022

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

NM_000466.2:c.2097dupT and NM_000466.2:c.2528G>A are the most common PEX1 variants; about 80% of persons with a PEX1 pathogenic variant have at least 1 of these common alleles. -

Apr 08, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PEX1 c.2097dupT (p.Ile700Tyrfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 77/120218 control chromosomes at a frequency of 0.0006405, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX1 variant (0.003873). The variant of interest is a common mutation that has been reported in multiple ZS affected homozygous and compound heterozygous individuals. Functional studies show that the variant results in the loss of protein function (Collins_1998). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

PEX1-related disorder Pathogenic:2

Sep 19, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also referred to as c.2098insT and I700Yfs*42 in the literature. This frameshifting variant in exon 13 of 24 introduces a premature stop codon and is predicted to result in loss of normal protein function through protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in the homozygous and compound heterozygous state in multiple individuals with Zellweger spectrum disorder (PMID: 10447258). This variant has been frequently reported in PEX1-deficient individuals (PMID: 17055079). Functional studies showed that this variant results in decreased mRNA levels and loss of protein function (PMID: 10447258). Loss-of-function variation in PEX1 is an established mechanism of disease (PMID: 9398847, 16086329, 16141001, 21031596, 26387595, 31831025). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.08% (1260/1613750). Based on the available evidence, the c.2097dupT (p.Ile700TyrfsTer42) variant is classified as Pathogenic. -

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PEX1 c.2097dupT variant is predicted to result in a frameshift and premature protein termination (p.Ile700Tyrfs*42). This variant has been reported in both the homozygous and compound heterozygous states in multiple patients with Zellweger syndrome (Maxwell et al. 2002. PubMed ID: 12402331; Berendse et al. 2016. PubMed ID: 26287655; Rush et al. 2016. PubMed ID: 26643206; Ghosh et al. 2017. PubMed ID: 28468868). Notably, one patient with this variant in the compound heterozygous state with another pathogenic PEX1 variant showed a milder phenotype with survival into adulthood (Berendse et al. 2016. PubMed ID: 26287655). However, two functional studies have reported that this variant severely affects peroxisomal function (Maxwell et al. 2002. PubMed ID: 12402331; Ratbi et al. 2015. PubMed ID: 26387595). This variant is reported in 0.092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, we interpret this variant as pathogenic. -

Zellweger spectrum disorders Pathogenic:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile700Tyrfs*42) 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 (rs61750415, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with peroxisomal biogenesis disorder (PMID: 10447258, 12402331, 26287655, 26387595, 26643206, 28468868). ClinVar contains an entry for this variant (Variation ID: 7519). For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2

Oct 15, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jul 18, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2097dupT (p.I700Yfs*42) alteration, located in exon 13 (coding exon 13) of the PEX1 gene, consists of a duplication of T at position 2097, causing a translational frameshift with a predicted alternate stop codon after 42 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the TT allele has an overall frequency of 0.05% (137/282532) total alleles studied. The highest observed frequency was 0.09% (119/128972) of European (non-Finnish) alleles. This mutation is common and has been reported in the homozygous and compound heterozygous state in numerous individuals with PEX1-related peroxisome biogenesis spectrum disorders (Collins, 1999; Steinberg, 2004; Rosewich, 2005; Ebberink, 2011). Based on the available evidence, this alteration is classified as pathogenic. -

Optic atrophy Pathogenic:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61750415; hg19: chr7-92132483;