ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2097dup (p.Ile700fs)

dbSNP: rs61750415
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Total submissions: 37
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000078918 SCV000329457 pathogenic not provided 2022-06-09 criteria provided, single submitter 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)
Eurofins Ntd Llc (ga) RCV000078918 SCV000331295 pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000500705 SCV000596391 pathogenic Peroxisome biogenesis disorder 2016-04-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000078918 SCV000609514 pathogenic not provided 2017-05-12 criteria provided, single submitter clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000007953 SCV000680330 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2021-07-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000500705 SCV000696794 pathogenic Peroxisome biogenesis disorder 2017-05-15 criteria provided, single submitter 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.
Invitae RCV001376645 SCV000754536 pathogenic Zellweger spectrum disorders 2024-01-31 criteria provided, single submitter 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.
Baylor Genetics RCV000850579 SCV000992801 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B 2017-12-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853332 SCV000996191 pathogenic Peroxisome biogenesis disorder 1B 2018-08-28 criteria provided, single submitter 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.
Baylor Genetics RCV001004324 SCV001163205 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Peroxisome biogenesis disorder 1B criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000007953 SCV001194190 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2019-12-04 criteria provided, single submitter 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
Blueprint Genetics RCV001073754 SCV001239314 pathogenic Retinal dystrophy 2017-10-15 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000078918 SCV001246668 pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing PEX1: PM3:Very Strong, PVS1, PM2
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000853332 SCV001368667 pathogenic Peroxisome biogenesis disorder 1B 2016-01-01 criteria provided, single submitter 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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV000007953 SCV001423858 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) criteria provided, single submitter 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).
Elsea Laboratory, Baylor College of Medicine RCV000850579 SCV001424268 pathogenic Peroxisome biogenesis disorder 1A (Zellweger); Heimler syndrome 1; Peroxisome biogenesis disorder 1B 2020-04-01 criteria provided, single submitter clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux RCV000078918 SCV001468912 pathogenic not provided criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000007953 SCV002061574 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2021-09-20 criteria provided, single submitter clinical testing PVS1, PS3, PM2
Mayo Clinic Laboratories, Mayo Clinic RCV000078918 SCV002525765 pathogenic not provided 2021-07-14 criteria provided, single submitter clinical testing PVS1, PS3, PS4_moderate
Centogene AG - the Rare Disease Company RCV000853332 SCV002598518 pathogenic Peroxisome biogenesis disorder 1B 2022-09-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000078918 SCV002817194 pathogenic not provided 2021-09-03 criteria provided, single submitter 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.
Ambry Genetics RCV002512885 SCV003634204 pathogenic Inborn genetic diseases 2021-04-20 criteria provided, single submitter 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.
Revvity Omics, Revvity Omics RCV000078918 SCV003824843 pathogenic not provided 2023-11-16 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000007953 SCV003839139 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2022-11-22 criteria provided, single submitter 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003335020 SCV004046411 pathogenic PEX1-RELATED DISORDERS criteria provided, single submitter clinical testing 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 state and in combination with other PEX1 variants in multiple patients with Zellweger spectrum disorder (PMID: 10447258). It is one of the most common PEX1 mutations in PEX1-deficient patients (PMID: 17055079). Functional studies confirm this variant results in decreased mRNA levels and loss of protein function (PMID: 10447258). The c.2097dupT (p.Ile700TyrfsTer42) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.05% (137/282532) and thus is presumed to be rare. Based on the available evidence, the c.2097dupT (p.Ile700TyrfsTer42) variant is classified as Pathogenic.
Preventiongenetics, part of Exact Sciences RCV003415676 SCV004114848 pathogenic PEX1-related condition 2023-08-04 criteria provided, single submitter 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 (http://gnomad.broadinstitute.org). In summary, we interpret this variant as pathogenic.
Baylor Genetics RCV000201307 SCV004203260 pathogenic Heimler syndrome 1 2023-10-28 criteria provided, single submitter clinical testing
OMIM RCV000007953 SCV000028158 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2015-10-01 no assertion criteria provided literature only
OMIM RCV000201307 SCV000256088 pathogenic Heimler syndrome 1 2015-10-01 no assertion criteria provided literature only
GeneReviews RCV000500705 SCV001478319 not provided Peroxisome biogenesis disorder no assertion provided 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000078918 SCV001741006 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000078918 SCV001808480 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000078918 SCV001922150 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000078918 SCV001957229 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000078918 SCV001972332 pathogenic not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001376645 SCV002076876 pathogenic Zellweger spectrum disorders 2017-03-17 no assertion criteria provided clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000201307 SCV004099366 pathogenic Heimler syndrome 1 2023-10-30 no assertion criteria provided clinical testing

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