POLG Q1236H - GET-Evidence

Curation:
Currentness:

POLG Q1236H

(POLG Gln1236His)


Short summary

Generally a nonpathogenic polymorphism, but may have a modifier effect that increases severity when combined in cis with other pathogenic variants.

Variant evidence
Computational 1

Polyphen 2 predicts disruptive effect

Functional 1

Stronger effect when combined with pathogenic variant

Case/Control

Insufficient data for case/control analysis

Familial -
 
Clinical importance
Severity 3

Unclear increased severity effect

Treatability -
Penetrance

The chances of having a pathogenic variant in combination with this variant is very low

See Luoma PT et al. 2005 (15917273).

 

Impact

Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

other

Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr15:89859994: 5.8% (626/10758) in EVS
  • A @ chr15:87660997: 3.1% (4/128) in GET-Evidence
  • Frequency shown in summary reports: 5.8% (626/10758)

Publications
 

Luoma PT, Luo N, Löscher WN, Farr CL, Horvath R, Wanschitz J, Kiechl S, Kaguni LS, Suomalainen A. Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet. 2005 Jul 15;14(14):1907-20. Epub 2005 May 25. PubMed PMID: 15917273.

Mentions this variant as a polymorphism that seems to have a modifier effect on another pathogenic variant: “When compared with the single R627Q mutant, the double-mutant R627Q/Q1236H enzyme showed ∼2-fold higher specific activity in the gapped DNA assay and 1.6-fold in the ssDNA assay”

Pagnamenta AT, Taanman JW, Wilson CJ, Anderson NE, Marotta R, Duncan AJ, Bitner-Glindzicz M, Taylor RW, Laskowski A, Thorburn DR, Rahman S. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod. 2006 Oct;21(10):2467-73. Epub 2006 Apr 4. PubMed PMID: 16595552.

Mentions this mutation as potentially having a modifier effect, but dismisses the possibility as it occurs in trans in the patient.

Genomes
 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
hom A @ chr15:89859994

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
hom A @ chr15:89859994

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het A @ chr15:89859994

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr15:89859994

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het A @ chr15:89859994

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr15:87660998

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr15:87660998

 

Other external references
 

    dbSNP
  • rs3087374
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • 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
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/POLG
    PolyPhen-2
  • Score: 0.937 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = –1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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