NM_002693.3(POLG):c.2542G>A (p.Gly848Ser) AND Mitochondrial DNA depletion syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 11, 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:
RCV003230362.8

Allele description [Variation Report for NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)]

NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)

Genes:
POLG:DNA polymerase gamma, catalytic subunit [Gene - OMIM - HGNC]
POLGARF:POLG alternative reading frame [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q26.1
Genomic location:
Preferred name:
NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)
Other names:
p.G848S:GGC>AGC; NM_001126131.1(POLG):c.2542G>A(p.Gly848Ser); NM_002693.2(POLG):c.2542G>A(p.Gly848Ser)
HGVS:
  • NC_000015.10:g.89321792C>T
  • NG_008218.2:g.18004G>A
  • NM_001126131.2:c.2542G>A
  • NM_002693.3:c.2542G>AMANE SELECT
  • NP_001119603.1:p.Gly848Ser
  • NP_002684.1:p.Gly848Ser
  • NP_002684.1:p.Gly848Ser
  • LRG_765t1:c.2542G>A
  • LRG_765:g.18004G>A
  • LRG_765p1:p.Gly848Ser
  • NC_000015.9:g.89865023C>T
  • NM_001126131.1:c.2542G>A
  • NM_002693.2:c.2542G>A
  • P54098:p.Gly848Ser
Protein change:
G848S; GLY848SER
Links:
UniProtKB: P54098#VAR_023675; OMIM: 174763.0006; dbSNP: rs113994098
NCBI 1000 Genomes Browser:
rs113994098
Molecular consequence:
  • NM_001126131.2:c.2542G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.2542G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mitochondrial DNA depletion syndrome
Synonyms:
mitochondrial DNA depletion
Identifiers:
MONDO: MONDO:0018158; MedGen: C0342782; OMIM: PS603041

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003929297Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 11, 2023) 		germlineclinical testing

PubMed (2)
[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

Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.

Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ.

J Med Genet. 2011 Oct;48(10):669-81. doi: 10.1136/jmedgenet-2011-100222. Epub 2011 Aug 31.

PubMed [citation]
PMID:
21880868

Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication.

Kasiviswanathan R, Longley MJ, Chan SS, Copeland WC.

J Biol Chem. 2009 Jul 17;284(29):19501-10. doi: 10.1074/jbc.M109.011940. Epub 2009 May 28.

PubMed [citation]
PMID:
19478085
PMCID:
PMC2740576

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003929297.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: POLG c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) 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 0.00015 in 251408 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome (0.00015 vs 0.0035), allowing no conclusion about variant significance. c.2542G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (e.g., Tang_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <1% of normal polymerase activity (e.g., Kasiviswanathan_2009). Multiple ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as 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: May 7, 2024