POLG
DNA polymerase gamma, catalytic subunit, the group of DNA polymerases|MicroRNA protein coding host genes
Basic information
Region (hg38): 15:89305198-89334861
Links
Phenotypes
GenCC
Source:
- mitochondrial DNA depletion syndrome 4a (Definitive), mode of inheritance: AR
- mitochondrial DNA depletion syndrome 4a (Definitive), mode of inheritance: AR
- sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (Definitive), mode of inheritance: AR
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (Definitive), mode of inheritance: AD
- mitochondrial DNA depletion syndrome 4a (Strong), mode of inheritance: AR
- mitochondrial DNA depletion syndrome 4a (Supportive), mode of inheritance: AR
- mitochondrial neurogastrointestinal encephalomyopathy (Supportive), mode of inheritance: AR
- sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (Supportive), mode of inheritance: AR
- recessive mitochondrial ataxia syndrome (Supportive), mode of inheritance: AR
- spinocerebellar ataxia with epilepsy (Supportive), mode of inheritance: AR
- autosomal recessive progressive external ophthalmoplegia (Supportive), mode of inheritance: AR
- autosomal dominant progressive external ophthalmoplegia (Supportive), mode of inheritance: AD
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (Definitive), mode of inheritance: AD
- progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (Strong), mode of inheritance: AD
- mitochondrial DNA depletion syndrome 4a (Strong), mode of inheritance: AR
- Leigh syndrome (Limited), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Mitochondrial DNA depletion syndrome 4B; Sensory ataxia, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4A (Alpers type); Alpers syndrome; POLG-related ataxia neuropathy spectrum disorders | AD/AR | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Audiologic/Otolaryngologic; Biochemical; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic | 14851183; 14467368; 2725645; 13971413; 6033104; 4647849; 1252162; 2246481; 2067633; 8368248; 7897414; 9894877; 11431686; 11571332; 12210792; 12297582; 12825077; 15351195; 15534189; 15122711; 15477547; 15929042; 15689359; 16177225; 16130100; 16634032; 17502560; 6957900; 18487244; 18195149; 19307547; 19752458; 20301791; 20558295; 20837861; 20837862; 20142534; 20220442; 21357833; 21670405 |
| Conditions can include cardiomyopathy; Hepatotoxic medications should be avoided |
ClinVar
This is a list of variants' phenotypes submitted to
- Progressive sclerosing poliodystrophy (129 variants)
- not provided (30 variants)
- 6 conditions (8 variants)
- Inborn genetic diseases (7 variants)
- Mitochondrial disease (6 variants)
- Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (5 variants)
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (4 variants)
- Mitochondrial DNA depletion syndrome 4b (4 variants)
- POLG-related disorder (3 variants)
- POLG-Related Spectrum Disorders (3 variants)
- Hereditary spastic paraplegia (3 variants)
- Mitochondrial DNA depletion syndrome (3 variants)
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (2 variants)
- Mitochondrial DNA depletion syndrome 4b;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy (2 variants)
- Tip-toe gait (1 variants)
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic (1 variants)
- Progressive sclerosing poliodystrophy;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Mitochondrial DNA depletion syndrome 4b (1 variants)
- Primary familial dilated cardiomyopathy (1 variants)
- Mitochondrial DNA depletion syndrome 4b;Progressive sclerosing poliodystrophy (1 variants)
- Neurodevelopmental delay (1 variants)
- Spinocerebellar ataxia with epilepsy (1 variants)
- Intellectual disability (1 variants)
- Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections (1 variants)
- Mitochondrial DNA depletion syndrome 4b;Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy (1 variants)
- Generalized epilepsy;Obesity;Global developmental delay (1 variants)
- Mitochondrial DNA depletion syndrome 4b;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;Progressive sclerosing poliodystrophy (1 variants)
- mitochondrial hepatopathy (1 variants)
- Childhood myocerebrohepatopathy spectrum (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLG 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 | 22 | 538 | 563 | |||
| missense | 25 | 81 | 1025 | 14 | 1150 | |
| nonsense | 42 | 20 | 66 | |||
| start loss | 2 | |||||
| frameshift | 58 | 42 | 106 | |||
| inframe indel | 57 | 18 | 78 | |||
| splice donor/acceptor (+/-2bp) | 12 | 31 | 45 | |||
| splice region | 2 | 1 | 44 | 88 | 1 | 136 |
| non coding | 47 | 388 | 61 | 497 | ||
| Total | 138 | 177 | 1165 | 958 | 69 |
Highest pathogenic variant AF is 0.000656
Variants in POLG
This is a list of pathogenic ClinVar variants found in the POLG region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 15-89305202-T-A | Fanconi anemia | Pathogenic (Aug 24, 2023) | ||
| 15-89305202-TG-T | Fanconi anemia complementation group I • Fanconi anemia | Pathogenic/Likely pathogenic (Nov 25, 2023) | ||
| 15-89305203-G-A | Fanconi anemia | Likely benign (Jan 15, 2024) | ||
| 15-89305203-G-T | Fanconi anemia | Uncertain significance (Aug 03, 2022) | ||
| 15-89305206-C-T | Fanconi anemia | Likely benign (Jan 09, 2024) | ||
| 15-89305213-A-G | Fanconi anemia | Uncertain significance (Nov 15, 2022) | ||
| 15-89305215-C-G | Inborn genetic diseases | Uncertain significance (Jun 10, 2024) | ||
| 15-89305217-A-G | Fanconi anemia | Uncertain significance (Nov 09, 2023) | ||
| 15-89305218-C-T | Fanconi anemia • Fanconi anemia complementation group I | Conflicting classifications of pathogenicity (Sep 10, 2023) | ||
| 15-89305219-G-A | Fanconi anemia | Uncertain significance (Jul 03, 2022) | ||
| 15-89305221-G-A | Fanconi anemia | Likely benign (Jan 27, 2022) | ||
| 15-89305222-C-A | Fanconi anemia | Uncertain significance (Mar 07, 2022) | ||
| 15-89305224-T-A | Fanconi anemia | Uncertain significance (Sep 03, 2023) | ||
| 15-89305227-G-A | Fanconi anemia | Likely benign (Mar 17, 2023) | ||
| 15-89305228-G-A | Fanconi anemia | Uncertain significance (Aug 09, 2022) | ||
| 15-89305235-T-C | Fanconi anemia | Uncertain significance (Aug 23, 2022) | ||
| 15-89305239-C-T | Fanconi anemia | Likely benign (Aug 28, 2023) | ||
| 15-89305240-C-T | Fanconi anemia • Fanconi anemia complementation group I | Pathogenic (Mar 04, 2024) | ||
| 15-89305245-A-G | Fanconi anemia | Uncertain significance (Aug 16, 2022) | ||
| 15-89305248-A-G | Fanconi anemia | Uncertain significance (Sep 20, 2020) | ||
| 15-89305249-T-TG | not specified • Fanconi anemia | Conflicting classifications of pathogenicity (Dec 06, 2023) | ||
| 15-89305252-T-C | Fanconi anemia | Likely benign (Jul 22, 2022) | ||
| 15-89305256-C-T | Fanconi anemia | Likely benign (Jul 20, 2023) | ||
| 15-89305323-C-G | Fanconi anemia | Likely benign (Dec 14, 2022) | ||
| 15-89305325-C-T | Fanconi anemia | Likely benign (Nov 13, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| POLG | protein_coding | protein_coding | ENST00000268124 | 22 | 18559 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 2.08e-9 | 1.00 | 125692 | 0 | 56 | 125748 | 0.000223 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.742 | 770 | 714 | 1.08 | 0.0000468 | 7999 |
| Missense in Polyphen | 310 | 329.51 | 0.94078 | 3713 | ||
| Synonymous | -1.77 | 331 | 292 | 1.13 | 0.0000196 | 2444 |
| Loss of Function | 4.54 | 27 | 67.1 | 0.402 | 0.00000343 | 715 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000755 | 0.000753 |
| Ashkenazi Jewish | 0.000199 | 0.000198 |
| East Asian | 0.000109 | 0.000109 |
| Finnish | 0.000142 | 0.000139 |
| European (Non-Finnish) | 0.000204 | 0.000202 |
| Middle Eastern | 0.000109 | 0.000109 |
| South Asian | 0.000294 | 0.000294 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA.;
- Disease
- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 1 (PEOA1) [MIM:157640]: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:12210792, ECO:0000269|PubMed:15351195, ECO:0000269|PubMed:15534189, ECO:0000269|PubMed:17420318, ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18575922}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive, 1 (PEOB1) [MIM:258450]: A severe form of progressive external ophthalmoplegia, a disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. It is clinically more heterogeneous than the autosomal dominant forms. {ECO:0000269|PubMed:11431686, ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15351195, ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16401742, ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16634032, ECO:0000269|PubMed:16639411}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM:607459]: A systemic disorder resulting from mitochondrial dysfunction associated with mitochondrial depletion in skeletal muscle and peripheral nerve tissue. The clinical triad of symptoms consists of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, the phenotype varies widely, even within the same family, and can also include myopathy, seizures, and hearing loss. {ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:14745080, ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15824347, ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:16919951}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 4A (MTDPS4A) [MIM:203700]: An autosomal recessive hepatocerebral syndrome due to mitochondrial dysfunction. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis. {ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15689359, ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 4B (MTDPS4B) [MIM:613662]: An autosomal recessive progressive multisystem disorder due to mitochondrial dysfunction. It is clinically characterized by chronic gastrointestinal dysmotility and pseudo- obstruction, cachexia, progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, and muscle weakness. {ECO:0000269|PubMed:12825077, ECO:0000269|PubMed:19307547}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:18828154}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459]: An autosomal recessive syndrome characterized by headaches and/or seizures manifesting in childhood or adolescence, cerebellar and sensory ataxia, dysarthria, and myoclonus manifesting in early adulthood. Neuropathological findings include spinocerebellar degeneration associated with cortical neuronal degeneration in advanced cases. {ECO:0000269|PubMed:26942291}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Nucleotide Metabolism;Purine metabolism;Pyrimidine metabolism
(Consensus)
Recessive Scores
- pRec
- 0.342
Intolerance Scores
- loftool
- 0.0147
- rvis_EVS
- -0.03
- rvis_percentile_EVS
- 50.58
Haploinsufficiency Scores
- pHI
- 0.238
- hipred
- N
- hipred_score
- 0.476
- ghis
- 0.538
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- E
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.656
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Polg
- Phenotype
- endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; hearing/vestibular/ear 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); muscle phenotype; digestive/alimentary phenotype; neoplasm; pigmentation phenotype; reproductive system 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); hematopoietic system phenotype; 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); embryo phenotype; skeleton phenotype; immune system phenotype;
Zebrafish Information Network
- Gene name
- polg
- Affected structure
- whole organism
- Phenotype tag
- abnormal
- Phenotype quality
- decreased life span
Gene ontology
- Biological process
- DNA metabolic process;DNA-dependent DNA replication;mitochondrial DNA replication;base-excision repair, gap-filling;aging;response to light stimulus;response to gamma radiation;response to hyperoxia;cellular response to glucose stimulus;DNA biosynthetic process;nucleic acid phosphodiester bond hydrolysis
- Cellular component
- mitochondrion;gamma DNA polymerase complex;protein-containing complex;mitochondrial nucleoid;terminal bouton
- Molecular function
- protease binding;DNA binding;chromatin binding;DNA-directed DNA polymerase activity;protein binding;3'-5' exonuclease activity