ClinVar Genomic variation as it relates to human health
NM_025136.4(OPA3):c.143-1G>C
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_025136.4(OPA3):c.143-1G>C
Variation ID: 4239 Accession: VCV000004239.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.32 19: 45553912 (GRCh38) [ NCBI UCSC ] 19: 46057170 (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 Apr 4, 2013 Apr 15, 2024 Dec 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_025136.4:c.143-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001017989.3:c.143-24456G>C intron variant NC_000019.10:g.45553912C>G NC_000019.9:g.46057170C>G NG_013332.1:g.35953G>C NG_141603.1:g.361C>G - Protein change
- Other names
- IVS1-1G>C
- IVS1AS, G-C, -1
- Canonical SPDI
- NC_000019.10:45553911:C:G
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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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
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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OPA3 | - | - |
GRCh38 GRCh37 |
525 | 584 |
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV000004461.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2017 | RCV001093243.16 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2023 | RCV000798887.6 |
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
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193878.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_025136.3(OPA3):c.143-1G>C is classified as pathogenic in the context of Costeff optic atrophy syndrome. Sources cited for classification include the following: PMID 15902555, 25201222, 11668429 and … (more)
NM_025136.3(OPA3):c.143-1G>C is classified as pathogenic in the context of Costeff optic atrophy syndrome. Sources cited for classification include the following: PMID 15902555, 25201222, 11668429 and 20350831. Classification of NM_025136.3(OPA3):c.143-1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jan 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Optic atrophy 3
3-Methylglutaconic aciduria type 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002789638.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209053.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 3
Optic atrophy 3
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: SCV000938526.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 1 of the OPA3 gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects an acceptor splice site in intron 1 of the OPA3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with 3-methylglutaconic aciduria (PMID: 11668429, 25201222, 26190011). ClinVar contains an entry for this variant (Variation ID: 4239). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2017)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250129.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2001)
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no assertion criteria provided
Method: literature only
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3-@METHYLGLUTACONIC ACIDURIA, TYPE III
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024634.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020 |
Comment on evidence:
Anikster et al. (2001) identified an acceptor splice site mutation in the OPA3 gene, IVS1-1G-C, as the cause of 3-methylglutaconic aciduria type III (MGCA3; 258501), … (more)
Anikster et al. (2001) identified an acceptor splice site mutation in the OPA3 gene, IVS1-1G-C, as the cause of 3-methylglutaconic aciduria type III (MGCA3; 258501), or optic atrophy plus syndrome, in several Iraqi Jewish patients. The mutation abolished mRNA expression in the patients' fibroblasts. The mutation was also detected in 8 of 85 healthy ethnically matched controls, yielding a carrier frequency of 1 in 10 and indicating a founder effect. In 14 patients with MGCA3, all except one of Iraqi Jewish descent, Yahalom et al. (2014) identified homozygosity for the IVS1-1G-C (c.143-1G-C) mutation in the OPA3 gene. In a 5-year-old girl, born of consanguineous Syrian Jewish parents, with MGCA3, Carmi et al. (2015) identified homozygosity for the c.143-1G-C mutation in the OPA3 gene. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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3-methylglutaconic aciduria type 3
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454621.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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3-Methylglutaconic aciduria type 3
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000041510.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Accounts for 100% of pathogenic variants of individuals of Iraqi Jewish origin with Costeff syndrome
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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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Costeff Syndrome. | Adam MP | - | 2020 | PMID: 20301646 |
Atypical presentation of Costeff syndrome-severe psychomotor involvement and electrical status epilepticus during slow wave sleep. | Carmi N | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2015 | PMID: 26190011 |
Costeff syndrome: clinical features and natural history. | Yahalom G | Journal of neurology | 2014 | PMID: 25201222 |
OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. | Huizing M | Molecular genetics and metabolism | 2010 | PMID: 20350831 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria. | Neas K | Journal of inherited metabolic disease | 2005 | PMID: 15902555 |
Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. | Anikster Y | American journal of human genetics | 2001 | PMID: 11668429 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs80356523 ...
HelpRecord last updated Apr 15, 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.