ClinVar Genomic variation as it relates to human health
NM_000286.3(PEX12):c.888_889del (p.Leu297fs)
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.888_889del (p.Leu297fs)
Variation ID: 92776 Accession: VCV000092776.25
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 17q12 17: 35575973-35575974 (GRCh38) [ NCBI UCSC ] 17: 33902992-33902993 (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 Jan 6, 2017 May 1, 2024 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000286.3:c.888_889del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000277.1:p.Leu297fs frameshift NM_000286.2:c.888_889del NC_000017.11:g.35575973AG[1] NC_000017.10:g.33902992AG[1] NG_008447.1:g.7662CT[1] - Protein change
- L297fs
- Other names
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- Canonical SPDI
- NC_000017.11:35575972:AGAG:AG
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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 |
508 | 518 |
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
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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 28, 2023 | RCV000078563.16 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000412263.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2020 | RCV000410739.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2016 | RCV000586945.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2022 | RCV002477223.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2021 | RCV002514382.2 |
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
(Jan 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510758.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Jul 21, 2016)
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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: SCV000696482.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PEX12 c.888_889delCT (p.Leu297Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX12 protein due to nonsense … (more)
Variant summary: The PEX12 c.888_889delCT (p.Leu297Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX12 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 8/121406 control chromosomes at a frequency of 0.0000659, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX12 variant (0.0015811). The variant has been identified in multiple affected individuals in heterozygous and homozygous state. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 16, 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: SCV000110419.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
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Pathogenic
(Jan 06, 2020)
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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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Myriad Genetics, Inc.
Accession: SCV001194154.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, … (more)
NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, 14571262, 15542397 and 21031596. Classification of NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) 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
(Jan 06, 2020)
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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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Myriad Genetics, Inc.
Accession: SCV001194155.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, … (more)
NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) is classified as pathogenic in the context of peroxisome biogenesis disorder type 3. Sources cited for classification include the following: PMID list all 9792857, 14571262, 15542397 and 21031596. Classification of NM_000286.2(PEX12):c.888_889delCT(L297Tfs*12) 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
(May 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Peroxisome biogenesis disorder type 3B
Peroxisome biogenesis disorder 3A (Zellweger)
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002786956.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 28, 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: SCV002526175.3
First in ClinVar: Jun 18, 2022 Last updated: Mar 11, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 63 amino acids are replaced with 11 different amino acids, and other loss-of-function variants … (more)
Frameshift variant predicted to result in protein truncation, as the last 63 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.887_888delTC using alternate nomenclature; This variant is associated with the following publications: (PMID: 31395954, 9792857, 34426522, 31589614, 21031596, 32005694, 34440436, 15542397, 29619570, 26094004, 14571262, 32483926) (less)
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Pathogenic
(Sep 19, 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: SCV004201434.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 23, 2020)
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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: SCV002016584.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 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:
germline
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Invitae
Accession: SCV001234961.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu297Thrfs*12) 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.Leu297Thrfs*12) in the PEX12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the PEX12 protein. This variant is present in population databases (rs398123301, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with PEX12-related conditions (PMID: 9792857, 14571262, 21031596, 25287621, 26094004). ClinVar contains an entry for this variant (Variation ID: 92776). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003699409.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.888_889delCT (p.L297Tfs*12) alteration, located in exon 3 (coding exon 3) of the PEX12 gene, consists of a deletion of 2 nucleotides from position 888 … (more)
The c.888_889delCT (p.L297Tfs*12) alteration, located in exon 3 (coding exon 3) of the PEX12 gene, consists of a deletion of 2 nucleotides from position 888 to 889, causing a translational frameshift with a predicted alternate stop codon after 12 amino acids. This alteration occurs at the 3' terminus of the PEX12 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 17% of the protein. Premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been detected in multiple individuals with PEX12-related peroxisome biogenesis disorder, in the homozygous state, the compound heterozygous state, and in the heterozygous state without a second alteration identified (Chang, 1998; Ebberink, 2011; Gootjes, 2004; Konkoová, 2015; Salpietro, 2015; Steinberg, 2004; Wojcik, 2019). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Nov 01, 1998)
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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: SCV000494456.4
First in ClinVar: Feb 06, 2017 Last updated: Nov 21, 2019 |
Comment on evidence:
In a patient (PBD098) with Zellweger syndrome (PBD3A; 614859) who died at the age of 1 month, Chang and Gould (1998) identified compound heterozygosity for … (more)
In a patient (PBD098) with Zellweger syndrome (PBD3A; 614859) who died at the age of 1 month, Chang and Gould (1998) identified compound heterozygosity for a premature termination mutation (R180X; 601758.0005) and a 2-bp deletion in exon 3, c.887_888delTC, that resulted in frameshift after amino acid residue 296 and termination after an additional 11 amino acids. Patient fibroblasts were completely deficient in peroxisomal matrix protein import. Konkolova et al. (2015) detected the c.887_888delTC mutation in compound heterozygosity with a novel 2-bp duplication (c.767_768dupAT; 601758.0012) in a patient from Slovakia with Zellweger syndrome. (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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Infant mortality: the contribution of genetic disorders. | Wojcik MH | Journal of perinatology : official journal of the California Perinatal Association | 2019 | PMID: 31395954 |
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 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PEX12 | - | - | - | - |
Text-mined citations for rs398123301 ...
HelpRecord last updated May 01, 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.