NM_002693.2(POLG):c.752C>T (p.Thr251Ile) AND POLG-Related Spectrum Disorders

Clinical significance:Pathogenic (Last evaluated: Jun 14, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_002693.2(POLG):c.752C>T (p.Thr251Ile)]

NM_002693.2(POLG):c.752C>T (p.Thr251Ile)

POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002693.2(POLG):c.752C>T (p.Thr251Ile)
Other names:
  • NC_000015.10:g.89330184G>A
  • NG_008218.2:g.9612C>T
  • NM_001126131.1:c.752C>T
  • NM_002693.2:c.752C>T
  • NP_001119603.1:p.Thr251Ile
  • NP_002684.1:p.Thr251Ile
  • LRG_765t1:c.752C>T
  • LRG_765:g.9612C>T
  • LRG_765p1:p.Thr251Ile
  • NC_000015.9:g.89873415G>A
  • NG_008218.1:g.9612C>T
  • P54098:p.Thr251Ile
Protein change:
T251I; THR251ILE
UniProtKB: P54098#VAR_023664; OMIM: 174763.0007; dbSNP: rs113994094
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_002693.2:c.752C>T - missense variant - [Sequence Ontology: SO:0001583]


POLG-Related Spectrum Disorders
MedGen: CN239393

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000394298Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
(Jun 14, 2016)
germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]


Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]

Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene.

Lamantea E, Zeviani M.

Ann Neurol. 2004 Sep;56(3):454-5. No abstract available.

PubMed [citation]
See all PubMed Citations (15)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000394298.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (15)


The c.752C>T (p.Thr251Ile) variant is well described in the literature and has been reported across 11 studies in which it has been found in 36 individuals affected with POLG-related spectrum disorders covering a wide range of phenotypes (Van Goethem et al., 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Gáti et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013). In all but one of the reported cases, the p.Thr251Ile variant has been found in cis with p.Pro587Leu as the complex allele [p.Thr251Ile; p.Pro587Leu]. Twenty-four of the reported cases are compound heterozygotes with a third variant in trans to the complex allele, five cases are homozygous for the complex allele and six are heterozygotes. The one instance where the p.Thr251Ile variant was found independently was in a compound heterozygote state with another missense variant in one individual (Gati et al. 2011). The complex allele has been found in 5/2040 control alleles and the p.Thr251Ile variant alone is reported at a frequency of 0.00337 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Thr251Ile variant is classified as pathogenic for POLG-related spectrum disorders when found as part of the complex allele and of unknown significance but suspicious for pathogenicity for POLG-related spectrum disorders when found independently.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 17, 2019

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