ClinVar Genomic variation as it relates to human health
NM_001127649.3(PEX26):c.292C>T (p.Arg98Trp)
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_001127649.3(PEX26):c.292C>T (p.Arg98Trp)
Variation ID: 2152 Accession: VCV000002152.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q11.21 22: 18079935 (GRCh38) [ NCBI UCSC ] 22: 18562701 (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 Feb 9, 2017 Feb 28, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001127649.3:c.292C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121121.1:p.Arg98Trp missense NM_001199319.2:c.292C>T NP_001186248.1:p.Arg98Trp missense NM_017929.6:c.292C>T NP_060399.1:p.Arg98Trp missense NC_000022.11:g.18079935C>T NC_000022.10:g.18562701C>T NG_008339.1:g.7016C>T Q7Z412:p.Arg98Trp - Protein change
- R98W
- Other names
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- Canonical SPDI
- NC_000022.11:18079934:C:T
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PEX26 | - | - |
GRCh38 GRCh37 |
538 | 630 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (2) |
criteria provided, single submitter
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Sep 1, 2022 | RCV000002234.4 | |
Pathogenic (4) |
criteria provided, single submitter
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Dec 6, 2017 | RCV000402285.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2018 | RCV000780589.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000812717.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 16, 2022 | RCV003390634.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2023 | RCV003472958.1 |
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
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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
(Nov 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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PEX26-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119503.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PEX26 c.292C>T variant is predicted to result in the amino acid substitution p.Arg98Trp. This variant has been reported as pathogenic for autosomal recessive peroxisome … (more)
The PEX26 c.292C>T variant is predicted to result in the amino acid substitution p.Arg98Trp. This variant has been reported as pathogenic for autosomal recessive peroxisome biogenesis disorder, and in the homozygous state the milder infantile Refsum disease (Matsumoto et al. 2003. PubMed ID: 12851857; Furuki et al. 2005. PubMed ID: 16257970; Berendse et al. 2015. PubMed ID: 26287655; Neuhaus et al. 2017. PubMed ID: 28944237). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-18562701-C-T). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 7A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201498.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 7A (Zellweger)
Peroxisome biogenesis disorder 7B
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000953040.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the PEX26 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the PEX26 protein (p.Arg98Trp). This variant is present in population databases (rs62641228, gnomAD 0.01%). This missense change has been observed in individual(s) with Zellweger spectrum disorder (PMID: 12717447, 12851857, 16257970, 26287655, 28944237). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2152). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PEX26 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PEX26 function (PMID: 12717447, 12851857, 26627908). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 06, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000342580.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Sep 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorders, Zellweger syndrome spectrum
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917986.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PEX26 c.292C>T (p.Arg98Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PEX26 c.292C>T (p.Arg98Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 277208 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PEX26 causing Zellweger Syndrome (6.5e-05 vs 0.0016), allowing no conclusion about variant significance. c.292C>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Ebberink_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in between 50%-90% of normal activity (Furuki_2006). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 7B
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573130.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Functional studies provide strong evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12717447 , 12851857 , 26627908). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002152). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Motor delay (present) , Cognitive impairment (present)
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Pathogenic
(Jun 01, 2005)
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no assertion criteria provided
Method: literature only
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PEROXISOME BIOGENESIS DISORDER 7B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022392.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 09, 2017 |
Comment on evidence:
In a patient (cell line GM11335) with neonatal adrenoleukodystrophy (NALD; see PBD7B, 614873), Matsumoto et al. (2003) identified a homozygous C-to-T transition at nucleotide 292 … (more)
In a patient (cell line GM11335) with neonatal adrenoleukodystrophy (NALD; see PBD7B, 614873), Matsumoto et al. (2003) identified a homozygous C-to-T transition at nucleotide 292 of the PEX26 gene, resulting in an arg98-to-trp (R98W) substitution. The mutation rendered PEX26 unstable and less able to participate in PEX6 (601498)-mediated interaction with PEX1 (602136). Transfection of wildtype PEX26 restored peroxisome biogenesis in fibroblasts from this patient. Matsumoto et al. (2003) identified this mutation in homozygosity in a second patient with NALD. Matsumoto et al. (2003) performed functional expression studies of the R98W mutation, which showed temperature-sensitive (30 degree C) import of catalase and thiolase. They noted that the findings correlated with the milder phenotype in the patient described by Matsumoto et al. (2003). In a patient (cell line GM16865) with infantile Refsum disease (see 614873), Matsumoto et al. (2003) identified compound heterozygosity for 2 mutations in the PEX26 gene: R98W and a 1-bp insertion, 255insT (608666.0007), resulting in a frameshift introducing a distinct 28-amino acid sequence. Functional coexpression studies of the 2 mutations showed temperature-sensitive (30 degrees C) import of catalase and thiolase. Weller et al. (2005) pointed out that in the 18 genotyped probands with peroxisome biogenesis disorder of complementation group 8 reported to that time, the R98W mutation accounted for 14 (39%) of the mutant PEX26 genes (10 patients in their study, 4 of whom overlapped with the 7 reported by Matsumoto et al. (2003), and 5 in the report of Steinberg et al. (2004)). The high frequency of R98W may represent a founder effect, as has been described for certain alleles in other peroxisome biogenesis disorder complementation groups (Braverman et al., 1997), or recurrent mutations at a CpG dinucleotide in codon 98 (CGG to TGG). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926388.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955939.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967439.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. | Neuhaus C | Molecular genetics & genomic medicine | 2017 | PMID: 28944237 |
Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood. | Berendse K | Journal of inherited metabolic disease | 2016 | PMID: 26287655 |
Conserved targeting information in mammalian and fungal peroxisomal tail-anchored proteins. | Buentzel J | Scientific reports | 2015 | PMID: 26627908 |
Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients. | Ebberink MS | Human mutation | 2010 | PMID: 19877282 |
Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex. | Furuki S | The Journal of biological chemistry | 2006 | PMID: 16257970 |
Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. | Weller S | American journal of human genetics | 2005 | PMID: 15858711 |
The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum. | Steinberg S | Molecular genetics and metabolism | 2004 | PMID: 15542397 |
Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. | Matsumoto N | American journal of human genetics | 2003 | PMID: 12851857 |
The pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA ATPase complexes to peroxisomes. | Matsumoto N | Nature cell biology | 2003 | PMID: 12717447 |
Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. | Braverman N | Nature genetics | 1997 | PMID: 9090381 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX26 | - | - | - | - |
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Text-mined citations for rs62641228 ...
HelpRecord last updated Mar 11, 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.