ClinVar Genomic variation as it relates to human health
NM_000286.3(PEX12):c.730_733dup (p.Leu245fs)
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_000286.3(PEX12):c.730_733dup (p.Leu245fs)
Variation ID: 371737 Accession: VCV000371737.21
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 17q12 17: 35576128-35576129 (GRCh38) [ NCBI UCSC ] 17: 33903147-33903148 (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 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000286.3:c.730_733dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000277.1:p.Leu245fs frameshift NM_000286.2:c.730_733dup NC_000017.11:g.35576130_35576133dup NC_000017.10:g.33903149_33903152dup NG_008447.1:g.7506_7509dup - Protein change
- L245fs
- Other names
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- Canonical SPDI
- NC_000017.11:35576128:AGGCA:AGGCAGGCA
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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.
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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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PEX12 | - | - |
GRCh38 GRCh37 |
505 | 515 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (1) |
criteria provided, single submitter
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Aug 16, 2016 | RCV000409475.2 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000410995.14 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2023 | RCV000728570.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2018 | RCV000781710.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335311.1 |
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
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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
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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
(Apr 17, 2018)
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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: SCV000856162.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Sep 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 3A (Zellweger)
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914758.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in … (more)
The PEX12 c.730_733dupGCCT (p.Leu245CysfsTer19) variant has been reported in two studies and identified in three patients in a compound heterozygous state and one patient in a heterozygous state, all with peroxisome biogenesis disorders, with three specifically noted to be in the Zellweger syndrome spectrum (Chang et al. 1997; Steinberg et al. 2004; Yik et al. 2009; Ebberink et al. 2011). All individuals with the variant in a compound heterozygous state had a second insertion variant. Control data are unavailable for the p.Leu245CysfsTer19 variant, but it is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. To evaluate the effect of PEX12 expression on peroxisomal protein import, Chang et al. (1997) used patient fibroblasts and noted that when the variant was present, cDNA expression was observed in the cytoplasm only; however, expression of PEX12 in these cells reversed the effect and import into the peroxisomes was observed. Based on the evidence and due to the potential impact of frameshift variants, the p.Leu245CysfsTer19 variant is classified as pathogenic for Zellweger syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Aug 02, 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: SCV000919973.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PEX12 c.730_733dupGCCT (p.Leu245CysfsX19) 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. A truncation downstream of this position have been classified as pathogenic by our laboratory, c.888_889delCT (p.Leu297fsX12). The variant allele was found at a frequency of 1.6e-05 in 244662 control chromosomes (gnomAD). The variant, c.730_733dupGCCT has been reported in the literature in individuals affected with Zellweger Syndrome spectrum disorders (Chang_1998, Cordoba_2018, Ebberink_2010,Yik_2009). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Chang_1998). A ClinVar submission from another 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
(Aug 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder type 3B
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487601.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Aug 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 3A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487602.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Jun 21, 2023)
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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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GeneDx
Accession: SCV002571593.3
First in ClinVar: Sep 17, 2022 Last updated: Jul 22, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 18 incorrect amino acids. Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 9090384, 19105186, 21031596, 19877282, 15542397, 9792857, 29389947) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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PEX12-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046226.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This frameshift variant is found in the last exon of PEX12 and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). Truncating variants located … (more)
This frameshift variant is found in the last exon of PEX12 and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). Truncating variants located downstream of this alteration have been reported in individuals with PEX12-related disorders in the literature (PMID: 26094004). This variant, also referred to as c.733-734insGCCT and c.733-734insGCC (p.L245Cfsx19), has been previously reported as a compound heterozygous change in two individuals with peroxisome biogenesis disorder (PMID: 9090384, 9792857, 15542397, 29389947, 21031596). The c.730_733dup (p.Leu245CysfsTer19) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/249910) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.730_733dup (p.Leu245CysfsTer19) variant is classified as Pathogenic. (less)
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 3A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201426.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder 3A (Zellweger)
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000950691.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu245Cysfs*19) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu245Cysfs*19) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs61752107, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with peroxisome biogenesis disorders (PMID: 9090384, 19105186). This variant is also known as c.733_734insGCCT. ClinVar contains an entry for this variant (Variation ID: 371737). Studies have shown that this premature translational stop signal alters PEX12 gene expression (PMID: 9090384). This variant disrupts a region of the PEX12 protein in which other variant(s) (p.Leu297Thrfs*12) have been determined to be pathogenic (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 1997)
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no assertion criteria provided
Method: literature only
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PEROXISOMAL BIOGENESIS DISORDER 3A (ZELLWEGER)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028419.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In fibroblasts from a patient (PBD097) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Chang et al. (1997) identified compound heterozygosity for a … (more)
In fibroblasts from a patient (PBD097) with peroxisome biogenesis disorder of complementation group 3 (PBD3A; 614859), Chang et al. (1997) identified compound heterozygosity for a 4-bp insertion after nucleotide 733 of the PEX12 gene and a single T insertion after nucleotide 744 (601758.0002). The 4-bp insertion creates a new Cac8I restriction site. (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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Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach. | Córdoba M | PloS one | 2018 | PMID: 29389947 |
A novel mutation in the PEX12 gene causing a peroxisomal biogenesis disorder. | Konkoľová J | Molecular biology reports | 2015 | PMID: 26094004 |
Zellweger syndrome and secondary mitochondrial myopathy. | Salpietro V | European journal of pediatrics | 2015 | PMID: 25287621 |
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 |
Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. | Yik WY | Human mutation | 2009 | PMID: 19105186 |
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 PEX12 gene of patients with a peroxisome biogenesis disorder. | Gootjes J | European journal of human genetics : EJHG | 2004 | PMID: 14571262 |
Phenotype-genotype relationships in complementation group 3 of the peroxisome-biogenesis disorders. | Chang CC | American journal of human genetics | 1998 | PMID: 9792857 |
Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders. | Chang CC | Nature genetics | 1997 | PMID: 9090384 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX12 | - | - | - | - |
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Text-mined citations for rs61752107 ...
HelpRecord last updated Apr 06, 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.