OPA1
OPA1 mitochondrial dynamin like GTPase
Basic information
Region (hg38): 3:193593143-193697811
Links
Phenotypes
GenCC
Source:
- optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (Strong), mode of inheritance: AD
- mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (Strong), mode of inheritance: AR
- autosomal dominant optic atrophy, classic form (Definitive), mode of inheritance: AD
- autosomal dominant optic atrophy plus syndrome (Supportive), mode of inheritance: AD
- autosomal dominant optic atrophy, classic form (Supportive), mode of inheritance: AD
- Behr syndrome (Strong), mode of inheritance: AR
- mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (Limited), mode of inheritance: AR
- optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (Strong), mode of inheritance: AD
- Behr syndrome (Strong), mode of inheritance: AR
- Leigh syndrome (Moderate), mode of inheritance: AR
- OPA1-related optic atrophy with or without extraocular features (Definitive), mode of inheritance: Semidominant
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Glaucoma, normal tension, susceptibility to | AD | Ophthalmologic; Pharmacogenomic | As IOP is normal and patients usually have good central vision, normal tension glaucoma is underdiagnosed tends to presents late, and genetic knowledge could allow preventive measures and treatment related to vision preservation; Agents that may contribute to glaucoma should be avoided | Audiologic/Otolaryngologic; Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic | 6493699; 4058877; 11017080; 11017079; 12566046; 15505825; 15531309; 16240368; 15781809; 16158427; 17306754; 18158317; 18496845; 18195150; 18065439; 19029523; 18287570; 19181907; 20417568; 20417570; 20157015; 21621262; 21636302; 20837821; 22776096; 22857269; 22042570; 22382025; 25012220; 25012222; 25146916; 26561570 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (1039 variants)
- Autosomal dominant optic atrophy classic form (169 variants)
- not specified (81 variants)
- Inborn genetic diseases (23 variants)
- Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (17 variants)
- Abortive cerebellar ataxia (17 variants)
- OPA1-related condition (16 variants)
- Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (7 variants)
- Retinal dystrophy (7 variants)
- Mitochondrial disease (4 variants)
- Auditory neuropathy (3 variants)
- Optic atrophy (3 variants)
- Tip-toe gait (2 variants)
- OPA1-Related Disorders (2 variants)
- Optic Atrophy, Dominant (2 variants)
- OPA1-related optic atrophy with or without extraocular features (2 variants)
- Dominant hereditary optic atrophy (1 variants)
- Glaucoma, normal tension, susceptibility to;Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;Abortive cerebellar ataxia;Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type);Autosomal dominant optic atrophy classic form (1 variants)
- Optic nerve dysplasia (1 variants)
- Abortive cerebellar ataxia;Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;Autosomal dominant optic atrophy classic form (1 variants)
- Abnormal brain morphology (1 variants)
- Retinitis pigmentosa (1 variants)
- Neurodevelopmental disorder (1 variants)
- Abortive cerebellar ataxia;Glaucoma, normal tension, susceptibility to;Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type);Autosomal dominant optic atrophy classic form;Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1 variants)
- Autosomal dominant cerebellar ataxia (1 variants)
- Childhood onset hearing loss (1 variants)
- Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type);Glaucoma, normal tension, susceptibility to;Autosomal dominant optic atrophy classic form;Abortive cerebellar ataxia (1 variants)
- 9 conditions (1 variants)
- Optic nerve hypoplasia (1 variants)
- Osteoporosis;Mildly elevated creatine kinase;Limb pain;Myotonia (1 variants)
- Autosomal dominant optic atrophy classic form;Abortive cerebellar ataxia;Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1 variants)
- Ocular impairment (1 variants)
- Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;Autosomal dominant optic atrophy classic form (1 variants)
- Stargardt disease (1 variants)
- Cone-rod dystrophy (1 variants)
- Abortive cerebellar ataxia;Glaucoma, normal tension, susceptibility to;Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy;Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type);Autosomal dominant optic atrophy classic form (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the OPA1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 125 | 139 | ||||
| missense | 15 | 27 | 296 | 56 | 400 | |
| nonsense | 38 | 13 | 56 | |||
| start loss | 1 | |||||
| frameshift | 63 | 14 | 80 | |||
| inframe indel | 13 | 15 | ||||
| splice donor/acceptor (+/-2bp) | 34 | 12 | 51 | |||
| splice region ? | 5 | 8 | 40 | 31 | 3 | 87 |
| non coding ? | 44 | 163 | 73 | 282 | ||
| Total | 151 | 70 | 372 | 345 | 86 |
Highest pathogenic variant AF is 0.0000263
Variants in OPA1
This is a list of pathogenic ClinVar variants found in the OPA1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 3-193593196-C-A | Autosomal dominant optic atrophy classic form | Uncertain significance (Apr 27, 2017) | ||
| 3-193593206-T-A | Autosomal dominant optic atrophy classic form | Benign (Jan 12, 2018) | ||
| 3-193593234-T-C | Autosomal dominant optic atrophy classic form | Uncertain significance (Jan 13, 2018) | ||
| 3-193593276-G-A | Autosomal dominant optic atrophy classic form | Uncertain significance (Jan 13, 2018) | ||
| 3-193593367-C-G | not specified | Likely benign (Feb 03, 2016) | ||
| 3-193593368-C-T | not specified • Autosomal dominant optic atrophy classic form | Conflicting classifications of pathogenicity (Apr 27, 2017) | ||
| 3-193593370-C-T | Autosomal dominant optic atrophy classic form • OPA1-related disorder | Conflicting classifications of pathogenicity (Aug 25, 2020) | ||
| 3-193593375-G-A | Autosomal dominant optic atrophy classic form • OPA1-related disorder | Uncertain significance (Jan 10, 2024) | ||
| 3-193593378-A-T | Likely pathogenic (Nov 11, 2022) | |||
| 3-193593380-G-A | Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy | Pathogenic (Jan 05, 2024) | ||
| 3-193593382-G-T | Uncertain significance (Apr 06, 2022) | |||
| 3-193593383-G-A | Likely pathogenic (Apr 09, 2023) | |||
| 3-193593384-C-T | Pathogenic (Jun 14, 2022) | |||
| 3-193593393-C-G | Uncertain significance (Apr 24, 2022) | |||
| 3-193593398-C-T | Likely benign (Oct 17, 2023) | |||
| 3-193593399-G-T | Autosomal dominant optic atrophy classic form | Uncertain significance (Dec 06, 2022) | ||
| 3-193593407-C-G | Likely benign (Dec 27, 2023) | |||
| 3-193593423-C-G | Likely benign (Feb 11, 2023) | |||
| 3-193593423-C-T | not specified • Autosomal dominant optic atrophy classic form | Benign/Likely benign (Jan 11, 2024) | ||
| 3-193593433-C-G | Inborn genetic diseases | Uncertain significance (May 10, 2021) | ||
| 3-193593695-C-T | Benign (Jul 15, 2018) | |||
| 3-193614631-C-CTGTG | Benign (Jun 28, 2018) | |||
| 3-193614715-T-C | not specified • OPA1-related disorder | Conflicting classifications of pathogenicity (Feb 14, 2024) | ||
| 3-193614715-T-G | Likely benign (Oct 02, 2023) | |||
| 3-193614727-G-A | Inborn genetic diseases | Uncertain significance (Oct 05, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| OPA1 | protein_coding | protein_coding | ENST00000361908 | 29 | 104680 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.986 | 0.0136 | 125713 | 0 | 35 | 125748 | 0.000139 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.97 | 411 | 540 | 0.761 | 0.0000291 | 6605 |
| Missense in Polyphen | 91 | 181.67 | 0.50091 | 2138 | ||
| Synonymous | 0.574 | 166 | 176 | 0.945 | 0.00000890 | 1757 |
| Loss of Function | 6.33 | 13 | 70.3 | 0.185 | 0.00000394 | 791 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000400 | 0.000398 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000382 | 0.000326 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000151 | 0.000141 |
| Middle Eastern | 0.000382 | 0.000326 |
| South Asian | 0.000196 | 0.000196 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission (PubMed:16778770, PubMed:17709429, PubMed:20185555, PubMed:24616225, PubMed:28746876). Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion (PubMed:17709429). Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation (PubMed:20185555). The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes (PubMed:20185555). Plays a role in remodeling cristae and the release of cytochrome c during apoptosis (By similarity). Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space (By similarity). Plays a role in mitochondrial genome maintenance (PubMed:20974897, PubMed:18158317). {ECO:0000250|UniProtKB:P58281, ECO:0000269|PubMed:16778770, ECO:0000269|PubMed:17709429, ECO:0000269|PubMed:18158317, ECO:0000269|PubMed:20185555, ECO:0000269|PubMed:20974897, ECO:0000269|PubMed:24616225, ECO:0000269|PubMed:28746876}.; FUNCTION: Isoforms that contain the alternative exon 4b (present in isoform 4 and isoform 5) are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane. {ECO:0000269|PubMed:20974897}.;
- Disease
- DISEASE: Optic atrophy 1 (OPA1) [MIM:165500]: A condition that features progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA1 is characterized by an insidious onset of visual impairment in early childhood with moderate to severe loss of visual acuity, temporal optic disk pallor, color vision deficits, and centrocecal scotoma of variable density. {ECO:0000269|PubMed:11017079, ECO:0000269|PubMed:11017080, ECO:0000269|PubMed:11440988, ECO:0000269|PubMed:11440989, ECO:0000269|PubMed:11810270, ECO:0000269|PubMed:12036970, ECO:0000269|PubMed:12566046, ECO:0000269|PubMed:14961560, ECO:0000269|PubMed:15948788, ECO:0000269|PubMed:16513463, ECO:0000269|PubMed:16617242, ECO:0000269|PubMed:18204809, ECO:0000269|PubMed:18360822, ECO:0000269|PubMed:19319978, ECO:0000269|PubMed:19325939, ECO:0000269|PubMed:19969356, ECO:0000269|PubMed:20185555, ECO:0000269|PubMed:22382025, ECO:0000269|PubMed:22857269, ECO:0000269|PubMed:23401657}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dominant optic atrophy plus syndrome (DOA+) [MIM:125250]: A neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia, muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes. {ECO:0000269|PubMed:15531309, ECO:0000269|PubMed:16240368, ECO:0000269|PubMed:18065439, ECO:0000269|PubMed:18158317, ECO:0000269|PubMed:18195150, ECO:0000269|PubMed:20185555, ECO:0000269|PubMed:21112924, ECO:0000269|PubMed:23387428}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Behr syndrome (BEHRS) [MIM:210000]: An autosomal recessive syndrome characterized by optic atrophy beginning in early childhood associated with ataxia, pyramidal signs, spasticity, mental retardation, and posterior column sensory loss. The ataxia, spasticity, and muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade. {ECO:0000269|PubMed:21636302, ECO:0000269|PubMed:25012220, ECO:0000269|PubMed:25146916}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 14, cardioencephalomyopathic type (MTDPS14) [MIM:616896]: An autosomal recessive mitochondrial disorder characterized by lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Skeletal muscle biopsies show significant mtDNA depletion and abnormal mitochondria. {ECO:0000269|PubMed:26561570}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Regulation of Apoptosis;Apoptosis;Programmed Cell Death
(Consensus)
Recessive Scores
- pRec
- 0.345
Intolerance Scores
- loftool
- 0.00854
- rvis_EVS
- -0.57
- rvis_percentile_EVS
- 18.96
Haploinsufficiency Scores
- pHI
- 0.389
- hipred
- Y
- hipred_score
- 0.563
- ghis
- 0.627
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.983
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |
Mouse Genome Informatics
- Gene name
- Opa1
- Phenotype
- mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; muscle phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype;
Zebrafish Information Network
- Gene name
- opa1
- Affected structure
- cardiac muscle cell
- Phenotype tag
- abnormal
- Phenotype quality
- increased size
Gene ontology
- Biological process
- mitochondrial genome maintenance;mitochondrial fission;dynamin family protein polymerization involved in mitochondrial fission;apoptotic process;mitochondrion organization;inner mitochondrial membrane organization;visual perception;mitochondrial fusion;positive regulation of mitochondrial fusion;positive regulation of neuron maturation;response to muscle activity;axonal transport of mitochondrion;calcium import into the mitochondrion;negative regulation of apoptotic process;GTP metabolic process;positive regulation of insulin receptor signaling pathway;intracellular distribution of mitochondria;protein complex oligomerization;response to electrical stimulus;retina development in camera-type eye;positive regulation of dendritic spine morphogenesis;membrane fusion;mitochondrion morphogenesis;cellular response to glucose stimulus;cellular response to hypoxia;cochlea development;negative regulation of release of cytochrome c from mitochondria;cellular senescence;membrane tubulation;negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway;response to curcumin;cellular response to L-glutamate
- Cellular component
- nucleoplasm;cytoplasm;mitochondrion;mitochondrial outer membrane;mitochondrial inner membrane;mitochondrial intermembrane space;cytosol;membrane;integral component of membrane;mitochondrial crista;dendrite;extrinsic component of mitochondrial inner membrane;mitochondrial membrane;axon cytoplasm
- Molecular function
- magnesium ion binding;GTPase activity;protein binding;GTP binding;microtubule binding;kinase binding;phosphatidic acid binding;cardiolipin binding