ClinVar Genomic variation as it relates to human health
NM_130837.3(OPA1):c.1034G>A (p.Arg345Gln)
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_130837.3(OPA1):c.1034G>A (p.Arg345Gln)
Variation ID: 5084 Accession: VCV000005084.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q29 3: 193637280 (GRCh38) [ NCBI UCSC ] 3: 193355069 (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 Aug 22, 2016 Feb 14, 2024 Oct 3, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_130837.3:c.1034G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_570850.2:p.Arg345Gln missense NM_001354663.2:c.500G>A NP_001341592.1:p.Arg167Gln missense NM_001354664.2:c.497G>A NP_001341593.1:p.Arg166Gln missense NM_015560.3:c.869G>A NP_056375.2:p.Arg290Gln missense NM_130831.3:c.761G>A NP_570844.1:p.Arg254Gln missense NM_130832.3:c.815G>A NP_570845.1:p.Arg272Gln missense NM_130833.3:c.872G>A NP_570846.1:p.Arg291Gln missense NM_130834.3:c.923G>A NP_570847.2:p.Arg308Gln missense NM_130835.3:c.926G>A NP_570848.1:p.Arg309Gln missense NM_130836.3:c.980G>A NP_570849.2:p.Arg327Gln missense NC_000003.12:g.193637280G>A NC_000003.11:g.193355069G>A NG_011605.1:g.49137G>A LRG_337:g.49137G>A LRG_337t1:c.869G>A LRG_337p1:p.Arg290Gln O60313:p.Arg290Gln - Protein change
- R345Q, R291Q, R166Q, R167Q, R272Q, R309Q, R327Q, R254Q, R308Q
- Other names
- R290Q
- Canonical SPDI
- NC_000003.12:193637279:G:A
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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
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
Help
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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OPA1 | - | - |
GRCh38 GRCh37 |
1234 | 1423 |
Conditions - Germline
Condition
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2022 | RCV000005389.16 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 3, 2023 | RCV000790668.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 18, 2018 | RCV001336297.9 |
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
(Jan 06, 2016)
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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: SCV000232749.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant optic atrophy classic form
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976724.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS3, PM1, PM2, PM5, PP2, PP3, PP5
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Likely pathogenic
(Jul 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001529646.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple affected … (more)
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple affected families [PMID 11017080, 22779427, 25564500, 21745197] Clinical variability has been previously reported and may be due to incomplete penetrance; some carriers can be unaffected [PMID 17724190, 12488262] (less)
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Likely pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762175.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Clinical Features:
Optic atrophy (present) , Leber optic atrophy (present)
Sex: female
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Pathogenic
(Sep 29, 2020)
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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: SCV001787297.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Functional studies support a deleterious effect on mitochondrial morphology and cellular reactive oxygen species level (Zhang et al., 2016; Olichon et al., 2007); Not observed … (more)
Functional studies support a deleterious effect on mitochondrial morphology and cellular reactive oxygen species level (Zhang et al., 2016; Olichon et al., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33300680, 27858935, 30293569, 22779427, 21745197, 23916084, 25564500, 11017080, 17167772, 26867657, 32025183) (less)
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Pathogenic
(Feb 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001880554.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study in mouse embryonic fibroblasts showed this variant caused significant decrease of mtDNA content and completely fragmented the mitochondrial network (PMID: 30293569). The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Jun 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant optic atrophy classic form
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580867.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM1, PM5, PS3_SUP, PM2_SUP, PP3, PP4
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Number of individuals with the variant: 2
Sex: male
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Pathogenic
(Oct 03, 2023)
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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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Invitae
Accession: SCV003525477.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 290 of the OPA1 protein (p.Arg290Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 290 of the OPA1 protein (p.Arg290Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant optic atrophy (PMID: 11017080, 11440988, 11810270, 22779427, 25564500). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg345Gln. ClinVar contains an entry for this variant (Variation ID: 5084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects OPA1 function (PMID: 17167772, 26867657). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2000)
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no assertion criteria provided
Method: literature only
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OPTIC ATROPHY 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025569.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a family from Cuba, Alexander et al. (2000) demonstrated that members with autosomal dominant optic atrophy (165500) had a G-to-A transition of nucleotide 869 … (more)
In a family from Cuba, Alexander et al. (2000) demonstrated that members with autosomal dominant optic atrophy (165500) had a G-to-A transition of nucleotide 869 in exon 8 of the OPA1 gene, predicting an arg290-to-gln amino acid change. (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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Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
Structural insights into G domain dimerization and pathogenic mutation of OPA1. | Yu C | The Journal of cell biology | 2020 | PMID: 32379273 |
Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models. | Del Dotto V | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 30293569 |
Multiethnic involvement in autosomal-dominant optic atrophy in Singapore. | Loo JL | Eye (London, England) | 2017 | PMID: 27858935 |
The OPA1 Gene Mutations Are Frequent in Han Chinese Patients with Suspected Optic Neuropathy. | Zhang AM | Molecular neurobiology | 2017 | PMID: 26867657 |
OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation. | Santarelli R | Brain : a journal of neurology | 2015 | PMID: 25564500 |
Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation. | Barboni P | American journal of ophthalmology | 2014 | PMID: 24907432 |
Dominant optic atrophy: novel OPA1 mutations and revised prevalence estimates. | Yu-Wai-Man P | Ophthalmology | 2013 | PMID: 23916084 |
Correlation between visual acuity and OCT-measured retinal nerve fiber layer thickness in a family with ADOA and an OPA1 mutation. | Russo A | Ophthalmic genetics | 2013 | PMID: 22779427 |
High frequency of OPA1 mutations causing high ADOA prevalence in south-eastern Sicily, Italy. | Gallus GN | Clinical genetics | 2012 | PMID: 21745197 |
Comprehensive cDNA study and quantitative transcript analysis of mutant OPA1 transcripts containing premature termination codons. | Schimpf S | Human mutation | 2008 | PMID: 17722006 |
Reduction of inner retinal thickness in patients with autosomal dominant optic atrophy associated with OPA1 mutations. | Ito Y | Investigative ophthalmology & visual science | 2007 | PMID: 17724190 |
Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis. | Olichon A | Journal of cellular physiology | 2007 | PMID: 17167772 |
Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. | Votruba M | The British journal of ophthalmology | 2003 | PMID: 12488262 |
Mutation spectrum and splicing variants in the OPA1 gene. | Delettre C | Human genetics | 2001 | PMID: 11810270 |
Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. | Toomes C | Human molecular genetics | 2001 | PMID: 11440989 |
OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. | Pesch UE | Human molecular genetics | 2001 | PMID: 11440988 |
OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. | Alexander C | Nature genetics | 2000 | PMID: 11017080 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=OPA1 | - | - | - | - |
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Text-mined citations for rs121908375 ...
HelpRecord last updated May 27, 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.