Table 8. [POLG Pathogenic Variants Referenced in This GeneReview]. - GeneReviews®

Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NM_002693.3 NP_002684.1	c.695G>A	p.Arg232His	Pathogenic variant that when in trans w/the p.[Trp748Ser;p.Glu1143Gly] haplotype causes AHS
c.1399G>A	p.Ala467Thr	Common pathogenic variant in POLG-related disorders; severely ↓ DNA polymerase (pol) gamma activity (4% of wild type pol gamma activity) by ↓ affinity for dNTPs & lowering catalytic activity [Chan et al 2005].
c.1760C>T	p.Pro587Leu	Common pathogenic variant; nearly always occurs w/p.Thr251Ile in cis (i.e., p.[Thr251Ile;Pro587Leu]) in affected persons & in general population. Individually, these variants cause an approximately 30% reduction in DNA polymerase activity, but together there is a synergistic impairment of polymerase function to levels about 5% of normal [DeBalsi et al 2017].
c.2243G>C	p.Trp748Ser	Common pathogenic variant that causes AHS, ANS, arPEO, & ataxia-neuropathy. Results in ↓ DNA polymerase activity, low processivity, & severe DNA binding defect, but normal POLG2 interactions [Chan et al 2006]. Note: (1) The p.Glu1143Gly variant in cis modulates the deleterious effect of p.Trp748Ser by partially rescuing activity & ↓ protein stability [Chan et al 2006]. AHS results when the p.[Trp748Ser;p.Glu1143Gly] haplotype occurs in trans with a different pathogenic variant on the other allele (e.g., p.Arg232His). (2) This pathogenic variant is a Finnish founder variant.
c.2542G>A	p.Gly848Ser	Common pathogenic variant that results in <1% polymerase activity & a defect in DNA binding function [Kasiviswanathan et al 2009]

Reference Sequences

DNA Nucleotide Change

Predicted Protein Change

Comment [Reference]

NM_002693.3
NP_002684.1

c.695G>A

p.Arg232His

Pathogenic variant that when in trans w/the p.[Trp748Ser;p.Glu1143Gly] haplotype causes AHS

c.1399G>A

p.Ala467Thr

Common pathogenic variant in POLG-related disorders; severely ↓ DNA polymerase (pol) gamma activity (4% of wild type pol gamma activity) by ↓ affinity for dNTPs & lowering catalytic activity [Chan et al 2005].

c.1760C>T

p.Pro587Leu

Common pathogenic variant; nearly always occurs w/p.Thr251Ile in cis (i.e., p.[Thr251Ile;Pro587Leu]) in affected persons & in general population. Individually, these variants cause an approximately 30% reduction in DNA polymerase activity, but together there is a synergistic impairment of polymerase function to levels about 5% of normal [DeBalsi et al 2017].

c.2243G>C

p.Trp748Ser

Common pathogenic variant that causes AHS, ANS, arPEO, & ataxia-neuropathy. Results in ↓ DNA polymerase activity, low processivity, & severe DNA binding defect, but normal POLG2 interactions [Chan et al 2006]. Note: (1) The p.Glu1143Gly variant in cis modulates the deleterious effect of p.Trp748Ser by partially rescuing activity & ↓ protein stability [Chan et al 2006]. AHS results when the p.[Trp748Ser;p.Glu1143Gly] haplotype occurs in trans with a different pathogenic variant on the other allele (e.g., p.Arg232His). (2) This pathogenic variant is a Finnish founder variant.

c.2542G>A

p.Gly848Ser

Common pathogenic variant that results in <1% polymerase activity & a defect in DNA binding function [Kasiviswanathan et al 2009]

From: POLG-Related Disorders

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