GeneBe

POLG

protein-coding

DNA polymerase gamma, catalytic subunit, the group of DNA polymerases|MicroRNA protein coding host genes

Gene summary

Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_002693.3

Inheritance

AD, AR

ClinVar variants

P:562U:1400B:763

Top phenotype

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 (MNGIE type); Sensory ataxia, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4A (Alpers type); Alpers syndrome; POLG-related ataxia neuropathy spectrum disorders

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr15:89,305,198-89,334,861

External References & Databases

Ensembl (ENSG00000140521)NCBI Gene (5428)OMIM (174763)HGNC:9179GenCCUniProt (P54098)AlphaFoldClinVar (POLG)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~29.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008003

Submitter: Orphanet

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between POLG and Leigh syndrome spectrum (LSS) was evaluated using the ClinGen Clinical Validity Framework as of March 23, 2020. The POLG gene encodes the catalytic subunit of DNA polymerase gamma, the only DNA polymerase in humans that replicates and repairs mitochondrial DNA. The POLG gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2009 (variants reported in PMID: 18828154; this case was first reported in 1996 in PMID: 9566823 with further details provided in 2002 in PMID: 12004863). Pathogenic variants in POLG are more commonly associated with a range of other clinical syndromes such as Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia syndrome (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). Of note, many cases in the literature were reviewed to look for evidence of LSS. Several additional cases were considered but were ultimately excluded as features were more consistent with Alpers-Huttenlocher syndrome than LSS. Evidence supporting the gene-disease relationship between POLG and LSS includes case-level data and experimental data. This curation included two variants identified in one case in one publication (PMID: 18828154). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression data, functional alteration in patient cells, and animal models (PMIDs: 16464011, 25613900, 16957900, 26519465). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 23, 2020 (SOP Version 7).

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0024528

Submitter: Ambry Genetics

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024528

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 4aDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: Ambry Genetics

mitochondrial DNA depletion syndrome 4aSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 4aSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: Orphanet

mitochondrial DNA depletion syndrome 4aSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 4bSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013350

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 4aSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011835

Submitter: Orphanet

mitochondrial neurogastrointestinal encephalomyopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017575

Submitter: Orphanet

recessive mitochondrial ataxia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019791

Submitter: Orphanet

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011835

Submitter: Ambry Genetics

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011835

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009783

Submitter: PanelApp Australia

sensory ataxic neuropathy, dysarthria, and ophthalmoparesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011835

Submitter: G2P

spinocerebellar ataxia with epilepsySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016809

Submitter: Orphanet

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024528

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0024528

Submitter: G2P

mitochondrial DNA depletion syndrome 4aDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008758

Submitter: G2P

autosomal recessive progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016810

Submitter: Orphanet

Clinical Genomic Database (CGD)

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 (MNGIE type); Sensory ataxia, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4A (Alpers type); Alpers syndrome; POLG-related ataxia neuropathy spectrum disordersAD/AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Comments: Conditions can include cardiomyopathy; Hepatotoxic medications should be avoided

Refs: 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; 21670405Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLG variants in ClinVar

58 Conditions Cataloged
Progressive sclerosing poliodystrophyTotal: 2893
not providedTotal: 1086
POLG-related disorderTotal: 612
not specifiedTotal: 418
Inborn genetic diseasesTotal: 304
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1Total: 221
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesisTotal: 215
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1Total: 212

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002693.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
23
clinvar
699
clinvar
12
clinvar
 735
missense
31
clinvar
169
clinvar
1358
clinvar
50
clinvar
2
clinvar
 1610
nonsense
71
clinvar
37
clinvar
4
clinvar
 112
start loss
1
clinvar
3
clinvar
 4
frameshift
126
clinvar
72
clinvar
8
clinvar
 206
splice donor/acceptor (+/-2bp)
9
clinvar
45
clinvar
4
clinvar
 58
Total2373251400749142725

Highest pathogenic variant AF is 0.001985099

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002693.3RefSeqNP_002684.122MANE Select
ENST00000268124.11EnsemblENSP00000268124.522MANE Select
NM_001126131.2RefSeqNP_001119603.122Standard
ENST00000442287.6EnsemblENSP00000399851.222Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
polgDanio rerio

Structure: whole organism

Quality: decreased life span

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Nucleotide Metabolism
  • Purine metabolism
  • Pyrimidine metabolism

Biological Process

  • DNA metabolic process
  • DNA-dependent DNA replication
  • mitochondrial DNA replication
  • base-excision repair, gap-filling
  • aging

Molecular Function

  • protease binding
  • DNA binding
  • chromatin binding
  • DNA-directed DNA polymerase activity
  • protein binding

Cellular Component

  • mitochondrion
  • gamma DNA polymerase complex
  • protein-containing complex
  • mitochondrial nucleoid
  • terminal bouton

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000268124
Coding exons
22
Length
18559
Individuals with no LoFs
125692
Homozygous LoFs
0
Heterozygous LoFs
56
Defined
125748
p
0.000223
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.7427707141.080.00004687999
Missense (PolyPhen)310329.510.940783713
Synonymous-1.773312921.130.00001962444
Loss of Function4.542767.10.4020.00000343715

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000260.00026rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000110.00011rare
Finnish0.000140.00014rare
European (Non-Finnish)0.000200.00020rare
South Asian0.000290.00029rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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.;

Recessive Scores

pRec
0.342

Intolerance Scores

LoFtool
0.0147
RVIS EVS
-0.03
RVIS percentile EVS
50.58

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.656

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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