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NM_002693.3(POLG):c.3287G>A (p.Arg1096His) AND POLG-Related Spectrum Disorders

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 17, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003479051.1

Allele description [Variation Report for NM_002693.3(POLG):c.3287G>A (p.Arg1096His)]

NM_002693.3(POLG):c.3287G>A (p.Arg1096His)

Gene:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.3(POLG):c.3287G>A (p.Arg1096His)
Other names:
p.R1096H:CGT>CAT
HGVS:
  • NC_000015.10:g.89318736C>T
  • NG_008218.2:g.21060G>A
  • NG_011736.1:g.79774C>T
  • NM_001126131.2:c.3287G>A
  • NM_002693.3:c.3287G>AMANE SELECT
  • NP_001119603.1:p.Arg1096His
  • NP_002684.1:p.Arg1096His
  • NP_002684.1:p.Arg1096His
  • LRG_765t1:c.3287G>A
  • LRG_500:g.79774C>T
  • LRG_765:g.21060G>A
  • LRG_765p1:p.Arg1096His
  • NC_000015.9:g.89861967C>T
  • NM_002693.2:c.3287G>A
  • P54098:p.Arg1096His
Protein change:
R1096H
Links:
UniProtKB: P54098#VAR_058894; dbSNP: rs368435864
NCBI 1000 Genomes Browser:
rs368435864
Molecular consequence:
  • NM_001126131.2:c.3287G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.3287G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
POLG-Related Spectrum Disorders
Identifiers:
MedGen: C4763519

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004222831Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Nov 17, 2023) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene.

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, et al.

Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18.

PubMed [citation]
PMID:
16621917

Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions.

Hou Y, Zhao X, Xie Z, Yu M, Lv H, Zhang W, Yuan Y, Wang Z.

Mol Genet Genomic Med. 2022 May;10(5):e1921. doi: 10.1002/mgg3.1921. Epub 2022 Mar 15.

PubMed [citation]
PMID:
35289132
PMCID:
PMC9034679
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004222831.1

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

Description

Variant summary: POLG c.3287G>A (p.Arg1096His) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251306 control chromosomes (i.e., 5 heterozygotes; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3287G>A has been reported in the literature in multiple compound heterozygous individuals as well as at least one homozygote affected with POLG-Related Spectrum Disorders (e.g., Horvath_2006, Schulte_2009, Savard_2013, Bijarnia-Mahay_2014, Hou_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16621917, 35289132, 19752458, 23873972, 25129007). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 14, 2025