NM_002693.2(POLG):c.2246T>C (p.Phe749Ser) AND POLG-Related Spectrum Disorders

Clinical significance:Likely pathogenic (Last evaluated: Apr 26, 2019)

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.2246T>C (p.Phe749Ser)]

NM_002693.2(POLG):c.2246T>C (p.Phe749Ser)

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.2246T>C (p.Phe749Ser)
Other names:
  • NC_000015.10:g.89323423A>G
  • NG_008218.2:g.16373T>C
  • NM_001126131.2:c.2246T>C
  • NM_002693.2:c.2246T>C
  • NP_001119603.1:p.Phe749Ser
  • NP_002684.1:p.Phe749Ser
  • LRG_765t1:c.2246T>C
  • LRG_765:g.16373T>C
  • LRG_765p1:p.Phe749Ser
  • NC_000015.9:g.89866654A>G
Protein change:
dbSNP: rs202037973
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001126131.2:c.2246T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.2:c.2246T>C - missense variant - [Sequence Ontology: SO:0001583]


POLG-Related Spectrum Disorders
MedGen: C4763519

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001451643Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Apr 26, 2019)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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



Molecular diagnosis of Alpers syndrome.

Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK.

J Hepatol. 2006 Jul;45(1):108-16. Epub 2006 Feb 20.

PubMed [citation]

Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase gamma.

Zsurka G, Baron M, Stewart JD, Kornblum C, Bös M, Sassen R, Taylor RW, Elger CE, Chinnery PF, Kunz WS.

J Neuropathol Exp Neurol. 2008 Sep;67(9):857-66. doi: 10.1097/NEN.0b013e3181839b2d.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV001451643.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


The POLG c.2246T>C (p.Phe749Ser) variant is a missense variant that has been reported in four studies, in which it is found in a compound heterozygous state in a total of six individuals, including in three with POLG deficiency, in one with autosomal recessive POLG-related disorders, in one with Alpers syndrome, and in one with some features of the Alpers-Huttenlocher syndrome (Nguyen et al. 2006; Zsurka et al. 2008; Milone et al. 2011; Tang et al. 2011). The p.Phe749Ser variant was absent from 100 control subjects and is reported at a frequency of 0.000681 in the African population of the Genome Aggregation Database. The p.Phe749Ser variant demonstrated reduced mitochondrial DNA copy numbers in patient blood and tissue samples (Zsurka et al. 2008). Muscle biopsies from the Alpers-Huttenlocher syndrome patient revealed large mtDNA deletions, however, the mitochondrial impairment in the muscle tissue could not be explained solely by deletions (Zsurka et al. 2008). The phe749 residue is in the linker region suggested to be involved in protein–protein interactions but is not critical for catalytic function of the enzyme (Euro et al. 2011). Based on the collective evidence, the p.Phe749Ser variant is classified as likely pathogenic for POLG-related spectrum disorders.

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

Last Updated: Aug 17, 2021

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