ClinVar Genomic variation as it relates to human health
NM_000318.3(PEX2):c.355C>T (p.Arg119Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000318.3(PEX2):c.355C>T (p.Arg119Ter)
Variation ID: 13704 Accession: VCV000013704.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.13 8: 76983824 (GRCh38) [ NCBI UCSC ] 8: 77896060 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Feb 14, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000318.3:c.355C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000309.2:p.Arg119Ter nonsense NM_001079867.1:c.355C>T NM_001079867.2:c.355C>T NP_001073336.2:p.Arg119Ter nonsense NM_001172086.2:c.355C>T NP_001165557.2:p.Arg119Ter nonsense NM_001172087.2:c.355C>T NP_001165558.2:p.Arg119Ter nonsense NC_000008.11:g.76983824G>A NC_000008.10:g.77896060G>A NG_008371.1:g.21465C>T - Protein change
- R119*
- Other names
- R118*
- PEX2, ARG118TER (rs61752123)
- Canonical SPDI
- NC_000008.11:76983823:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00014
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PEX2 | - | - |
GRCh38 GRCh37 |
475 | 516 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000014703.36 | |
Pathogenic (2) |
no assertion criteria provided
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Aug 16, 2016 | RCV000032924.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2017 | RCV000589554.1 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001275872.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2023 | RCV002223176.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2022 | RCV002496363.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 5A (Zellweger)
Peroxisome biogenesis disorder 5B
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811101.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 5A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201464.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696558.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PEX2 c.355C>T (p.Arg119X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX2 protein due to nonsense … (more)
Variant summary: The PEX2 c.355C>T (p.Arg119X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0002708 (34/125548 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX2 variant (0.001118). Several publications have cited the variant in patients with diagnoses that are confirmed with standard biochemical tests. Additionally, a functional study demonstrated a lack of peroxisome formation via immunofluorescence in cultured fibroblasts of a patient who was homozygous for the variant of interest (Imamura_AJHG_1998). Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 5A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194007.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000318.2(PEX2):c.355C>T(R119*) is classified as pathogenic in the context of peroxisome biogenesis disorder type 5. Sources cited for classification include the following: PMID 15542397, 1546315 and … (more)
NM_000318.2(PEX2):c.355C>T(R119*) is classified as pathogenic in the context of peroxisome biogenesis disorder type 5. Sources cited for classification include the following: PMID 15542397, 1546315 and 14630978. Classification of NM_000318.2(PEX2):c.355C>T(R119*) 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. (less)
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Pathogenic
(Jun 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501450.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004237810.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 5A (Zellweger)
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000949919.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg119*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg119*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752123, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorders (PMID: 1546315, 7681622, 9452066, 9585609, 10528859, 15542397, 21465523, 23430938). ClinVar contains an entry for this variant (Variation ID: 13704). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 16, 2016)
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no assertion criteria provided
Method: clinical testing
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Peroxisome biogenesis disorder 5B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487550.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Zellweger syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001461519.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Apr 01, 2014)
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no assertion criteria provided
Method: literature only
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PEROXISOME BIOGENESIS DISORDER 5A (ZELLWEGER)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034958.8
First in ClinVar: Apr 04, 2013 Last updated: Sep 12, 2021 |
Comment on evidence:
Peroxisome Biogenesis Disorder 5A (Zellweger) By sequencing PAF1 from patient M.M. with Zellweger syndrome (PBD5A; 614866), Shimozawa et al. (1992) found a C-to-T mutation at … (more)
Peroxisome Biogenesis Disorder 5A (Zellweger) By sequencing PAF1 from patient M.M. with Zellweger syndrome (PBD5A; 614866), Shimozawa et al. (1992) found a C-to-T mutation at nucleotide 355 (counting from the first nucleotide of the initiator methionine codon). This resulted in change of codon 118 from CGA (arg) to TGA (stop). When PAF1 cDNA from M.M. was transfected back into her own fibroblasts, correction did not result. Both parents, who were not known to be related but came from the same village, were heterozygous for the mutation. By complementation studies, Shimozawa et al. (1993) demonstrated their group F is the same as complementation group 10 of Moser et al. (1995). They demonstrated, furthermore, that PAF1 transfected into fibroblasts of the Dutch patient reported by Brul et al. (1988) resulted in the formation of normal peroxisomes. Furthermore, they showed that the cells of the Dutch patient were homozygous for the same 355C-T mutation as in the Japanese patient. In a female infant, born to nonconsanguineous Ashkenazi Jewish parents, with Zellweger syndrome, Gootjes et al. (2004) identified homozygosity for the R119X mutation. Her sister also had Zellweger syndrome. Both sibs died in early infancy. Peroxisome Biogenesis Disorder 5B Shimozawa et al. (1999) identified the R119X mutation in compound heterozygosity with a missense mutation (170993.0002) in a patient with infantile Refsum disease (see 614867). In a 51-year-old Italian man, born of unrelated parents, with PBD5B manifest as childhood-onset cerebellar ataxia and an axonal sensorimotor polyneuropathy, Mignarri et al. (2012) identified compound heterozygosity for the R119X mutation and a 1-bp insertion (c.865_866insA; 170993.0006) in the PEX2 gene. Patient fibroblasts showed mosaicism for a peroxisomal defect, but further functional studies were not performed. Variant Population Genetics By screening 2,093 individuals of Ashkenazi Jewish descent from an ultra-Orthodox community through the use of TaqMan genotyping assays, real-time PCR, and allelic discrimination, Fedick et al. (2014) found a carrier frequency of 0.813% (+/-0.3.85%) for the c.355C-T mutation (rs61752123) in the PEX2 gene. They suggested that this mutation be used in screening panels for this population. (less)
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Pathogenic
(Apr 01, 2014)
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no assertion criteria provided
Method: literature only
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PEROXISOME BIOGENESIS DISORDER 5B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056696.8
First in ClinVar: Apr 04, 2013 Last updated: Sep 12, 2021 |
Comment on evidence:
Peroxisome Biogenesis Disorder 5A (Zellweger) By sequencing PAF1 from patient M.M. with Zellweger syndrome (PBD5A; 614866), Shimozawa et al. (1992) found a C-to-T mutation at … (more)
Peroxisome Biogenesis Disorder 5A (Zellweger) By sequencing PAF1 from patient M.M. with Zellweger syndrome (PBD5A; 614866), Shimozawa et al. (1992) found a C-to-T mutation at nucleotide 355 (counting from the first nucleotide of the initiator methionine codon). This resulted in change of codon 118 from CGA (arg) to TGA (stop). When PAF1 cDNA from M.M. was transfected back into her own fibroblasts, correction did not result. Both parents, who were not known to be related but came from the same village, were heterozygous for the mutation. By complementation studies, Shimozawa et al. (1993) demonstrated their group F is the same as complementation group 10 of Moser et al. (1995). They demonstrated, furthermore, that PAF1 transfected into fibroblasts of the Dutch patient reported by Brul et al. (1988) resulted in the formation of normal peroxisomes. Furthermore, they showed that the cells of the Dutch patient were homozygous for the same 355C-T mutation as in the Japanese patient. In a female infant, born to nonconsanguineous Ashkenazi Jewish parents, with Zellweger syndrome, Gootjes et al. (2004) identified homozygosity for the R119X mutation. Her sister also had Zellweger syndrome. Both sibs died in early infancy. Peroxisome Biogenesis Disorder 5B Shimozawa et al. (1999) identified the R119X mutation in compound heterozygosity with a missense mutation (170993.0002) in a patient with infantile Refsum disease (see 614867). In a 51-year-old Italian man, born of unrelated parents, with PBD5B manifest as childhood-onset cerebellar ataxia and an axonal sensorimotor polyneuropathy, Mignarri et al. (2012) identified compound heterozygosity for the R119X mutation and a 1-bp insertion (c.865_866insA; 170993.0006) in the PEX2 gene. Patient fibroblasts showed mosaicism for a peroxisomal defect, but further functional studies were not performed. Variant Population Genetics By screening 2,093 individuals of Ashkenazi Jewish descent from an ultra-Orthodox community through the use of TaqMan genotyping assays, real-time PCR, and allelic discrimination, Fedick et al. (2014) found a carrier frequency of 0.813% (+/-0.3.85%) for the c.355C-T mutation (rs61752123) in the PEX2 gene. They suggested that this mutation be used in screening panels for this population. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detection of unusual very-long-chain fatty acid and ether lipid derivatives in the fibroblasts and plasma of patients with peroxisomal diseases using liquid chromatography-mass spectrometry. | Takashima S | Molecular genetics and metabolism | 2017 | PMID: 28089346 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
Carrier frequency of two BBS2 mutations in the Ashkenazi population. | Fedick A | Clinical genetics | 2014 | PMID: 23829372 |
A deleterious mutation in the PEX2 gene causes Zellweger syndrome in individuals of Ashkenazi Jewish descent. | Fedick A | Clinical genetics | 2014 | PMID: 23590336 |
Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations. | Mignarri A | JIMD reports | 2012 | PMID: 23430938 |
Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations. | Dranchak PK | Journal of cellular biochemistry | 2011 | PMID: 21465523 |
The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. | Steinberg S | Molecular genetics and metabolism | 2004 | PMID: 15542397 |
Novel mutations in the PEX2 gene of four unrelated patients with a peroxisome biogenesis disorder. | Gootjes J | Pediatric research | 2004 | PMID: 14630978 |
Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders. | Shimozawa N | Journal of medical genetics | 1999 | PMID: 10528859 |
Temperature-sensitive phenotypes of peroxisome-assembly processes represent the milder forms of human peroxisome-biogenesis disorders. | Imamura A | American journal of human genetics | 1998 | PMID: 9585609 |
A novel mutation, R125X in peroxisome assembly factor-1 responsible for Zellweger syndrome. | Shimozawa N | Human mutation | 1998 | PMID: 9452066 |
Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. | Moser AB | The Journal of pediatrics | 1995 | PMID: 7541833 |
Standardization of complementation grouping of peroxisome-deficient disorders and the second Zellweger patient with peroxisomal assembly factor-1 (PAF-1) defect. | Shimozawa N | American journal of human genetics | 1993 | PMID: 7681622 |
A human gene responsible for Zellweger syndrome that affects peroxisome assembly. | Shimozawa N | Science (New York, N.Y.) | 1992 | PMID: 1546315 |
Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis. | Brul S | The Journal of clinical investigation | 1988 | PMID: 2454948 |
Shimozawa, N., Masuno, M., Suzuki, Y., Orii, T., Imaizumi, K., Kuroki, T., Tsukamoto, T., Osumi, T., Fujiki, Y. A human gene of Zellweger syndrome is mapped to chromosome 8q21.1. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A947, 1993. | - | - | - | - |
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Text-mined citations for rs61752123 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.