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NM_002693.3(POLG):c.2554C>T (p.Arg852Cys) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 31, 2022
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:
RCV002517007.3

Allele description [Variation Report for NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)]

NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)

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.2554C>T (p.Arg852Cys)
Other names:
p.R852C:CGC>TGC
HGVS:
  • NC_000015.10:g.89321780G>A
  • NG_008218.2:g.18016C>T
  • NM_001126131.2:c.2554C>T
  • NM_002693.3:c.2554C>TMANE SELECT
  • NP_001119603.1:p.Arg852Cys
  • NP_002684.1:p.Arg852Cys
  • NP_002684.1:p.Arg852Cys
  • LRG_765t1:c.2554C>T
  • LRG_765:g.18016C>T
  • LRG_765p1:p.Arg852Cys
  • NC_000015.9:g.89865011G>A
  • NM_002693.2:c.2554C>T
Protein change:
R852C
Links:
dbSNP: rs144500145
NCBI 1000 Genomes Browser:
rs144500145
Molecular consequence:
  • NM_001126131.2:c.2554C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002693.3:c.2554C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003681268Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(May 31, 2022) 		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

Molecular diagnosis of Alpers syndrome.

Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK.

J Hepatol. 2006 Jul;45(1):108-16. Epub 2006 Feb 20.

PubMed [citation]
PMID:
16545482

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
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003681268.2

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

Description

The c.2554C>T (p.R852C) alteration is located in exon 16 (coding exon 15) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 2554, causing the arginine (R) at amino acid position 852 to be replaced by a cysteine (C). Based on the available evidence, the POLG c.2554C>T (p.R852C) alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, the association of this alteration with autosomal dominant progressive external ophthalmoplegia is unlikely. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (13/282784) total alleles studied. The highest observed frequency was 0.01% (13/129132) of European (non-Finnish) alleles. This alteration has been reported in the compound heterozygous state in individuals with autosomal recessive POLG-related mitochondrial disorders (Hunter, 2011; Nguyen, 2006; Papandreou, 2018; St&ouml;dberg, 2020). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest that this alteration impairs DNA binding affinity and polymerase activity (Kasiviswanathan, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Jun 9, 2024