POLG G517V - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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(POLG Gly517Val)

Short summary

This variant has been associated with POLG-related neuropathy/ataxia, but recent reports contradict the originally published hypothesis of dominant pathogenic effect. It has been seen heterozygously in healthy relatives of affected individiuals; it may be a modifier gene or act in a recessive manner, or it may be a benign polymorphism.

Variant evidence
Computational 3

Gene associated with disease, NBLOSUM=5, polyphen predicts a damaging effect.

See Horvath R et al. 2006 (16621917).

Functional -
Case/Control 1

Although combined case/control data has high significance, only looking at studies that performed matched controls this drops to 0.07.

See Horvath R et al. 2006 (16621917), Wong LJ et al. 2008 (18546365), Blok MJ et al. 2009 (19578034), Schulte C et al. 2009 (19752458).


Not enough familial evidence, contradicts dominant hypothesis.

See Horvath R et al. 2006 (16621917), Blok MJ et al. 2009 (19578034).

Clinical importance
Severity 5
Treatability 1
Penetrance -


Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Total cases/controls case+ case– control+ control– p-value odds ratio
POLG-Related Disorders
13 633 1 974 0.0001 20.003


Allele frequency

  • A @ chr15:89870178: 0.5% (59/10758) in EVS
  • Frequency shown in summary reports: 0.5% (59/10758)


Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E, Prokisch H, Lochmüller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, Suomalainen A, Zeviani M, Chinnery PF. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18. PubMed PMID: 16621917.

In a screen of 38 individuals with mitochondrial disorders, this variant was found in a familial case from Central Europe. The 58yo father had neuropathy, the proband (26yo female) was compound heterozygous (E1143G) had neuropathy, ataxia and exercise intolerance and the 8yo daughter had epilepsy. Transmission was dominant despite the variant being in the linker region, while most previously reported dominant variants were in the polymerase domain. This variant was not seen in 337 Italians or 301 Finnish, but was seen in 1/336 German controls.

Cases/controls case+ case– control+ control– p-value odds ratio
POLG-Related Disorders
1 37 1 974 0.0737 26.324


Sarzi E, Bourdon A, Chrétien D, Zarhrate M, Corcos J, Slama A, Cormier-Daire V, de Lonlay P, Munnich A, Rötig A. Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. J Pediatr. 2007 May;150(5):531-4, 534.e1-6. PubMed PMID: 17452231.

In a screen of 100 children, this mutation was seen in one child with psychomotor retardation, as well as in her healthy father. Since the variant was previously reported to cause different symptoms (ataxia and neuropathy) in a dominant fashion, the authors say this suggests it may be a non-pathogenic polymorphism.

Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008 Jun 10;29(9):E150-E172. [Epub ahead of print] PubMed PMID: 18546365.

In a screen of 350 patients with phenotypes consistent with POLG-related ataxias, this variant was identified in 5 individuals as the sole mutation and in two individuals as a compound heterozygote in presumptive recessive cases. Controls were only used for the novel mutations. The authors conclude that “it is not clear whether this allele represents a benign polymorphism, or may be contributing to disease by poorly understood mechanisms, which allow it to function either as a dominant or a recessive allele.”

Cases/controls case+ case– control+ control– p-value odds ratio
POLG-Related Disorders
7 343 - - - -


Blok MJ, van den Bosch BJ, Jongen E, Hendrickx A, de Die-Smulders CE, Hoogendijk JE, Brusse E, de Visser M, Poll-The BT, Bierau J, de Coo IF, Smeets HJ. The unfolding clinical spectrum of POLG mutations. J Med Genet. 2009 Nov;46(11):776-85. Epub 2009 Jul 2. PubMed PMID: 19578034.

In a screen of 232, 4 unrelated patients were found to carry this variant. However, the inheritance pattern in the families did not support a dominant pattern of inheritance. The authors conclude “the p.G517V should be considered as an unclassified sequence variant for which the clinical relevance is currently unclear”.

Cases/controls case+ case– control+ control– p-value odds ratio
POLG-Related Disorders
4 228 - - - -


Schulte C, Synofzik M, Gasser T, Schöls L. Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations. Neurology. 2009 Sep 15;73(11):898-900. PubMed PMID: 19752458.

In a screen of 26 individuals with ataxias for variants in POLG, this variant was seen in 50f (dx 44yo) with cerebellar ataxia plus external ophthalmoplegia. She was the only individual with this phenotype. Controls for this variant are not mentioned.

Cases/controls case+ case– control+ control– p-value odds ratio
POLG-Related Disorders
1 25 - - - -



Other external references

  • GeneTests records for the POLG gene
    Progressive External Ophthalmoplegia with Mitochondrial DNA Dele
    Alpers-Huttenlocher Syndrome
    POLG-Related Disorders
    POLG-Related Sensory Ataxic Neuropathy, Dysarthria, and Ophthalm
  • Score: 0.025 (benign)
    Web search results (18 hits -- see all)
  • The unfolding clinical spectrum of POLG mutations.
    Mutations in the nuclear encoded polymerase-gamma (POLG) gene turn out to be a major ... and dominant nature of the previously reported p.G517V mutation, ...
  • A polymorphic polymerase -- DiMauro et al. 129 (7): 1637 -- Brain
    Specifically, polymerase (POLG) is in charge of replicating the mitochondrial ... POLG is made of three subunits, one catalytic subunit, POLG proper, ...
  • A polymorphic polymerase
    other terms with the same root apply to POLG: polymeric ... ventional and convenient subdivision of the POLG gene into. three distinct regions does ...
  • Mitochondrial Disorders
    l Polymerase, DNA, Gamma (POLG; POLG1) ; Chromosome 15q25; Dominant or Recessive ... POLG protein. Catalytic subunit of mitochondrial DNA polymerase ...
  • POLG Mutations Affect mtDNA Synthesis
    subunit, POLG, have been shown to be associated with aging and various diseases by ... Three cell lines contained no variation in wild type (normal) POLG. ...
  • DNA Polymerase Gamma Mutations in Male Infertility and Ageing
    The nuclear encoded catalytic subunit of polymerase gamma (POLG) is the only ... exonuclease domain of Polg were shown to have a three- to five-fold increase in ...
  • Modulation of the W748S mutation in DNA polymerase g by the ...
    mutations in POLG, the gene encoding the catalytic subunit of pol g, have been ... W748S mutation in POLG is the most common mutation in ataxia-neuropathy spectrum ...
  • Phenotypic variations in 3 children with POLG1 mutations.
    Department of Pediatrics and Neurology, Nationwide Children's Hospital, The Ohio ... mutations: heterozygous p.G517V in 2 half siblings and heterozygous p. ...
  • Studio nel sistema modello Saccharomyces cerevisiae di ...
    mutazioni patologiche nel gene POLG codificante la DNA. polimerasi mitocondriale ... occorre che non i raggi del sole né i dardi lucenti del giorno ...

Other in silico analyses

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 2

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Gene search

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