ClinVar Miner

Submissions for variant NM_000466.3(PEX1):c.2097dup (p.Ile700fs) (rs61750415)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000078918 SCV000329457 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing The c.2097dupT variant in the PEX1 gene has been reported previously, sometimes as c.2098insT (Steinberg et al., 2017). This variant is one of the most common pathogenic variants in the PEX1 gene, and in the homozygous state it is usually associated with a severe phenotype (Steinberg et al., 2017). The c.2097dupT variant causes a frameshift starting with codon Isoleucine 700, changes this amino acid to a Tyrosine residue, and creates a premature Stop codon at position 42 of the new reading frame, denoted p.Ile700TyrfsX42. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.2097dupT as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 disorders, Zellweger syndrome spectrum 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000500705 SCV000696794 pathogenic Peroxisome biogenesis disorders, Zellweger syndrome spectrum 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 syndrome 2020-11-02 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. This variant is present in population databases (rs61750415, ExAC 0.1%). This variant has been reported as homozygous or in combination with another PEX1 variant in many individuals affected with a peroxisomal biogenesis disorder (PMID: 10447258, 26643206, 26287655, 12402331, 26387595, 28468868). ClinVar contains an entry for this variant (Variation ID: 7519). Loss-of-function variants in PEX1 are known to be pathogenic (PMID: 9398847, 16086329, 16141001, 21031596). 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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000078918 SCV001246668 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
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
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000078918 SCV001468048 pathogenic not provided 2020-09-11 criteria provided, single submitter clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux RCV000078918 SCV001468912 pathogenic not provided 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
Institute of Human Genetics, Klinikum rechts der Isar RCV000007953 SCV000680330 pathogenic Peroxisome biogenesis disorder 1A (Zellweger) 2017-11-16 no assertion criteria provided clinical testing
GeneReviews RCV001290260 SCV001478319 pathogenic Peroxisome biogenesis disorders 2020-10-27 no assertion criteria 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

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