Variant summary: PEX26 c.34dupC (p.Leu12ProfsX103) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-05 in 206458 control chromosomes (gnomAD). c.34dupC has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink 2010, Matsumoto 2003). These data indicate that the variant is likely to be associated with disease. Functional studies indicate the variant impedes peroxisomal localization, catalase import, stability and binding to the Pex6p and Pex1p proteins (Furuki 2006). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001127649.3(PEX26):c.34dup (p.Leu12fs)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_001127649.3(PEX26):c.34dup (p.Leu12fs)
Variation ID: 2154 Accession: VCV000002154.21
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 22q11.21 22: 18078404-18078405 (GRCh38) [ NCBI UCSC ] 22: 18561170-18561171 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 17, 2024 Mar 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001127649.3:c.34dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001121121.1:p.Leu12fs frameshift NM_001199319.2:c.34dup NP_001186248.1:p.Leu12fs frameshift NM_017929.5:c.29dupC NM_017929.5:c.34dupC NM_017929.6:c.34dup NP_060399.1:p.Leu12fs frameshift NC_000022.11:g.18078410dup NC_000022.10:g.18561176dup NG_008339.1:g.5491dup NG_008339.2:g.5422dup NG_201355.1:g.157dup - Protein change
- L12fs
- Other names
- -
- Canonical SPDI
- NC_000022.11:18078404:CCCCCC:CCCCCCC
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| PEX26 | - | - |
GRCh38 GRCh37 |
544 | 638 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV000002237.8 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 14, 2022 | RCV000727235.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2018 | RCV000662021.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 4, 2018 | RCV000780590.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 8, 2023 | RCV000821185.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706843.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Oct 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Peroxisome biogenesis disorders, Zellweger syndrome spectrum
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917987.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PEX26 c.34dupC (p.Leu12ProfsX103) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PEX26 c.34dupC (p.Leu12ProfsX103) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-05 in 206458 control chromosomes (gnomAD). c.34dupC has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink 2010, Matsumoto 2003). These data indicate that the variant is likely to be associated with disease. Functional studies indicate the variant impedes peroxisomal localization, catalase import, stability and binding to the Pex6p and Pex1p proteins (Furuki 2006). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 27, 2018)
|
criteria provided, single submitter
Method: research
|
Peroxisome biogenesis disorder 7A (Zellweger)
Affected status: yes
Allele origin:
inherited
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV000891762.1 First in ClinVar: Jul 29, 2018 Last updated: Jul 29, 2018 |
Comment:
ACMG codes: PVS1, PM2, PP4, PP5
Number of individuals with the variant: 1
Clinical Features:
Oligohydramnios (present) , Micrognathia (present) , Abnormality of the face (present) , Wide anterior fontanel (present) , Large posterior fontanelle (present) , Abnormal eye morphology … (more)
Oligohydramnios (present) , Micrognathia (present) , Abnormality of the face (present) , Wide anterior fontanel (present) , Large posterior fontanelle (present) , Abnormal eye morphology (present) , Hypertelorism (present) , Micrognathia (present) , Redundant neck skin (present) , Low-set ears (present) , Lissencephaly (present) , Abnormality of brain morphology (present) , Seizures (present) , Talipes equinovarus (present) (less)
|
|
|
Pathogenic
(Dec 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Peroxisome biogenesis disorder 7B
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369715.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
|
|
|
Pathogenic
(Jul 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016586.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Peroxisome biogenesis disorder 7A (Zellweger)
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784352.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(Mar 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Peroxisome biogenesis disorder 7B
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784353.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(May 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002513547.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate significantly reduced catalase activity and defective peroxisomal localization (Furuki S et al., 2006); Frameshift variant predicted to result in protein truncation … (more)
Published functional studies demonstrate significantly reduced catalase activity and defective peroxisomal localization (Furuki S et al., 2006); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16257970, 12851857) (less)
|
|
|
Pathogenic
(Oct 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000961934.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu12Profs*103) in the PEX26 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu12Profs*103) in the PEX26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 12851857). This variant is also known as T35insC. ClinVar contains an entry for this variant (Variation ID: 2154). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Peroxisome biogenesis disorder 7A (Zellweger)
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201503.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 01, 2003)
|
no assertion criteria provided
Method: literature only
|
PEROXISOME BIOGENESIS DISORDER 7A (ZELLWEGER)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022395.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In a patient (cell line GM07371) with Zellweger syndrome (PBD7A; 614872), Matsumoto et al. (2003) identified compound heterozygosity for mutations in the PEX26 gene: one … (more)
In a patient (cell line GM07371) with Zellweger syndrome (PBD7A; 614872), Matsumoto et al. (2003) identified compound heterozygosity for mutations in the PEX26 gene: one allele carried a homozygous 1-bp insertion, T35insC, that resulted in a frameshift introducing a 102-amino acid sequence distinct from normal PEX26, and the other allele carried the T35insC mutation as well as a 147-bp deletion of nucleotides 668-814 resulting in deletion of amino acids 223-271 (del223-271). Functional expression studies of the 35insC mutation showed almost normal catalase and thiolase import. Coexpression studies of the complex allele showed weak temperature-sensitive (30 degree C) import of catalase. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
ACMG codes: PVS1, PM2, PP4, PP5
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
Published functional studies demonstrate significantly reduced catalase activity and defective peroxisomal localization (Furuki S et al., 2006); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16257970, 12851857)
Comment:
This sequence change creates a premature translational stop signal (p.Leu12Profs*103) in the PEX26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 12851857). This variant is also known as T35insC. ClinVar contains an entry for this variant (Variation ID: 2154). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
Variant summary: PEX26 c.34dupC (p.Leu12ProfsX103) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.9e-05 in 206458 control chromosomes (gnomAD). c.34dupC has been reported in the literature in individuals affected with Zellweger Syndrome (Ebberink 2010, Matsumoto 2003). These data indicate that the variant is likely to be associated with disease. Functional studies indicate the variant impedes peroxisomal localization, catalase import, stability and binding to the Pex6p and Pex1p proteins (Furuki 2006). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ACMG codes: PVS1, PM2, PP4, PP5
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
Published functional studies demonstrate significantly reduced catalase activity and defective peroxisomal localization (Furuki S et al., 2006); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16257970, 12851857)
Comment:
This sequence change creates a premature translational stop signal (p.Leu12Profs*103) in the PEX26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX26 are known to be pathogenic (PMID: 12851857, 21031596). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 12851857). This variant is also known as T35insC. ClinVar contains an entry for this variant (Variation ID: 2154). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. | Ebberink MS | Human mutation | 2011 | PMID: 21031596 |
| 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 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX26 | - | - | - | - |
Text-mined citations for rs61752129 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.