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NM_002693.3(POLG):c.1491G>C (p.Gln497His) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 25, 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:
RCV003230363.8

Allele description [Variation Report for NM_002693.3(POLG):c.1491G>C (p.Gln497His)]

NM_002693.3(POLG):c.1491G>C (p.Gln497His)

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.1491G>C (p.Gln497His)
Other names:
p.Q497H:CAG>CAC
HGVS:
  • NC_000015.10:g.89327006C>G
  • NG_008218.2:g.12790G>C
  • NM_001126131.2:c.1491G>C
  • NM_002693.3:c.1491G>CMANE SELECT
  • NP_001119603.1:p.Gln497His
  • NP_002684.1:p.Gln497His
  • NP_002684.1:p.Gln497His
  • LRG_765t1:c.1491G>C
  • LRG_765:g.12790G>C
  • LRG_765p1:p.Gln497His
  • NC_000015.9:g.89870237C>G
  • NM_001126131.1:c.1491G>C
  • NM_002693.2:c.1491G>C
  • P54098:p.Gln497His
Protein change:
Q497H; GLN497HIS
Links:
UniProtKB: P54098#VAR_023669; OMIM: 174763.0016; dbSNP: rs121918052
NCBI 1000 Genomes Browser:
rs121918052
Molecular consequence:
  • NM_001126131.2:c.1491G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.1491G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003929296Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Apr 25, 2023) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

Stranneheim H, Lagerstedt-Robinson K, Magnusson M, Kvarnung M, Nilsson D, Lesko N, Engvall M, Anderlid BM, Arnell H, Johansson CB, Barbaro M, Björck E, Bruhn H, Eisfeldt J, Freyer C, Grigelioniene G, Gustavsson P, Hammarsjö A, Hellström-Pigg M, Iwarsson E, Jemt A, Laaksonen M, et al.

Genome Med. 2021 Mar 17;13(1):40. doi: 10.1186/s13073-021-00855-5.

PubMed [citation]
PMID:
33726816
PMCID:
PMC7968334

Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.

Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC.

Hum Mutat. 2008 Sep;29(9):E150-72. doi: 10.1002/humu.20824.

PubMed [citation]
PMID:
18546365
PMCID:
PMC2891192
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929296.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: POLG c.1491G>C (p.Gln497His) results in a non-conservative amino acid change in 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 0.00013 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (0.00013 vs 0.0035), allowing no conclusion about variant significance. c.1491G>C has been reported in the literature in individuals affected with POLG-Related conditions who carried other variants in cis as well as pathogenic variants in trans. These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15824347, 33726816, 18546365, 25025039, 32391929, 18991199, 26942291, 21357833, 25065347). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Oct 8, 2024