ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.875T>A (p.Leu292Ter) (rs1805137)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000008222 SCV000236510 pathogenic Rhizomelic chondrodysplasia punctata type 1 2014-11-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000008222 SCV000248509 pathogenic Rhizomelic chondrodysplasia punctata type 1 2014-10-10 criteria provided, single submitter clinical testing
GeneDx RCV000339271 SCV000329459 pathogenic not provided 2018-04-13 criteria provided, single submitter clinical testing The L292X nonsense pathogenic variant in the PEX7 gene accounts for approximately 50% of rhizomelic chondrodysplasia punctata type 1 (Braverman et al., 2001). The L292X variant is observed in 84/126576 (0.066%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). This variant is predicted to cause a premature stop codon, resulting in protein truncation of the last 32 amnio acids. We interpret L292X as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000339271 SCV000331429 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000352824 SCV000460548 pathogenic PEX7-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The PEX7 c.875T>A (p.Leu292Ter) variant is a stop-gained variant that is well described as a pathogenic variant, accounting for 51% of disease alleles in individuals with rhizomelic chondrodysplasia punctata (Bravermann et al. 2012). The p.Leu292Ter variant is described in at least ten studies and found in a total of at least 187 individuals including 107 in a homozygous state, 47 in a compound heterozygous state, and 33 individuals in a heterozygous state (Braverman et al. 1997; Motley et al. 1997; Purdue et al. 1997; Brites et al. 1998; Shimozawa et al. 1999; Braverman et al. 2000; Motley et al. 2002; Braverman et al. 2002; Huffnagel et al. 2013; Jacobsen et al. 2016). The variant was absent from 41 controls but is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. The high frequency of the p.Leu292Ter allele is secondary to a founder effect in individuals of Northern European descent. Functional studies showed that the p.Leu292Ter variant protein is localized to the peroxisomes in contrast to the cystolic location of the wild type protein (Bravermann et al. 2012). The variant protein was also shown to be inactive in restoring defective PTS2 import in fibroblasts from patients and Chinese hamster ovary cells and to be impaired in binding both PST2 and PEX5 (Motley et al. 1997; Purdue et al. 1997; Mukai et al. 2002). Based on the collective evidence and the potential impact of stop-gained variants, the p.Leu292Ter variant is classified as pathogenic for PEX7-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000339271 SCV000493517 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515356 SCV000611237 pathogenic Phytanic acid storage disease; Rhizomelic chondrodysplasia punctata type 1; Peroxisome biogenesis disorder 9B 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008222 SCV000696493 pathogenic Rhizomelic chondrodysplasia punctata type 1 2016-12-08 criteria provided, single submitter clinical testing Variant summary: The PEX7 c.875T>A (p.Leu292X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX7 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest has been indicated to be a known founder mutation arising from an ancestral chromosome in the Caucasian population per Braverman_2000. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/121346 (1/4045), which does not exceed the estimated maximal expected allele frequency for a pathogenic PEX7 variant of 1/534. The variant of interest has been reported in multiple affected individuals in a homozygous and compound heterozygous state. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."
Invitae RCV000380952 SCV000776820 pathogenic Peroxisome biogenesis disorder 9B 2020-11-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PEX7 gene (p.Leu292*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 32 amino acids of the PEX7 protein. This variant is present in population databases (rs1805137, ExAC 0.04%). This variant has been reported as homozygous or in combination with other PEX7 variants in multiple individuals affected with rhizomelic chondrodysplasia punctata and has been described as a founder mutation in Northern Europe (PMID: 9090381, 9090382, 23572185, 22008564, 10083738, 21990100, 25800479). ClinVar contains an entry for this variant (Variation ID: 7780). Experimental studies have shown that this missense change prevents binding of the encoded receptor to type-2 peroxisomal targeting signal (PTS2) and the subsequent import of PTS2 to peroxisomes (PMID: 9090381, 11756410, 9090382). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000008222 SCV001163004 pathogenic Rhizomelic chondrodysplasia punctata type 1 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000008222 SCV001194024 pathogenic Rhizomelic chondrodysplasia punctata type 1 2019-11-12 criteria provided, single submitter clinical testing NM_000288.3(PEX7):c.875T>A(L292*) is classified as pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 9090383, 21465523, 10673331, 12325024, 11781871 and 9090381. Classification of NM_000288.3(PEX7):c.875T>A(L292*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285494 SCV001471931 pathogenic none provided 2019-10-07 criteria provided, single submitter clinical testing The PEX7 c.875T>A; p.Leu292Ter variant (rs1805137) accounts for about 50% of disease alleles in individuals affected with rhizomelic chondrodysplasia punctata type 1, and is reported in the literature in many affected individuals in the homozygous and compound heterozygous state (Braverman 1997, Braverman 2000, Jacobsen 2015, Motley 2002). This variant is reported in ClinVar (Variation ID: 7780), and is found in the general population with an overall allele frequency of 0.034% (96/282696 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein, since functional analyses of the variant protein show normal expression but a loss of function due to an inability to bind to the PTS2 ligand (Braverman 1997, Mukai 2002). Based on available information, this variant is considered to be pathogenic. References: Braverman et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet. 1997 Apr;15(4):369-76. Braverman N et al. PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics. 2000 Jan 15;63(2):181-92. Jacobsen JC et al. Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1. Case Rep Genet. 2015;2015:454526. Motley AM et al. Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet. 2002 Mar;70(3):612-24. Mukai S et al. Intracellular localization, function, and dysfunction of the peroxisome-targeting signal type 2 receptor, Pex7p, in mammalian cells. J Biol Chem. 2002 Mar 15;277(11):9548-61.
OMIM RCV000008222 SCV000028429 pathogenic Rhizomelic chondrodysplasia punctata type 1 2002-03-01 no assertion criteria provided literature only
GeneReviews RCV000008222 SCV000055662 pathologic Rhizomelic chondrodysplasia punctata type 1 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477898 SCV000536707 pathogenic Rhizomelic chondrodysplasia punctata type 1; Peroxisome biogenesis disorder 9B 2016-08-16 no assertion criteria provided research
Natera, Inc. RCV000008222 SCV001459669 pathogenic Rhizomelic chondrodysplasia punctata type 1 2020-09-16 no assertion criteria provided clinical testing

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