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NM_002693.2(POLG):c.2554C>T

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Interpretation:
Conflicting interpretations of pathogenicity​

Pathogenic(6);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
10 (Most recent: Sep 28, 2021)
Last evaluated:
Sep 23, 2021
Accession:
VCV000206528.14
Variation ID:
206528
Description:
single nucleotide variant
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NM_002693.3(POLG):c.2554C>T (p.Arg852Cys)

Allele ID
202960
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q26.1
Genomic location
15: 89321780 (GRCh38) GRCh38 UCSC
15: 89865011 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_765:g.18016C>T
LRG_765t1:c.2554C>T LRG_765p1:p.Arg852Cys
NM_002693.2:c.2554C>T NP_002684.1:p.Arg852Cys missense
... more HGVS
Protein change
R852C
Other names
p.R852C:CGC>TGC
Canonical SPDI
NC_000015.10:89321779:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Links
ClinGen: CA316701
dbSNP: rs144500145
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 2 criteria provided, multiple submitters, no conflicts Oct 1, 2018 RCV000633537.3
Pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000762953.1
Conflicting interpretations of pathogenicity 6 criteria provided, conflicting interpretations Sep 23, 2021 RCV000188581.10
Uncertain significance 1 no assertion criteria provided Jan 1, 2019 RCV001252349.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
POLG - - GRCh38
GRCh37
1350 1469

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 02, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000610294.1
Submitted: (Oct 05, 2017)
Evidence details
Pathogenic
(Oct 01, 2018)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000886909.1
Submitted: (Nov 16, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The NM_002693.2:c.2554C>T (NP_002684.1:p.Arg852Cys) [GRCH38: NC_000015.10:g.89321780G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1
Progressive sclerosing poliodystrophy
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Mitochondrial DNA depletion syndrome 1 (MNGIE type)
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mitochondrial DNA depletion syndrome 4B, MNGIE type
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000893385.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Aug 08, 2018)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Invitae
Accession: SCV000754783.3
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (10)
Comment:
This sequence change replaces arginine with cysteine at codon 852 of the POLG protein (p.Arg852Cys). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Nov 20, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV001145154.1
Submitted: (Sep 25, 2019)
Evidence details
Publications
PubMed (7)
Comment:
The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found … (more)
Pathogenic
(Sep 23, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000242203.13
Submitted: (Sep 28, 2021)
Evidence details
Comment:
Published functional studies of R852C demonstrate polymerase assays retained less than 1% that of wildtype polymerase activity, demonstrating a damaging effect (Kasiviswanathan et al., 2009); … (more)
Uncertain significance
(Feb 01, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001149562.7
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Jan 01, 2019)
no assertion criteria provided
Method: clinical testing
Intellectual disability
Allele origin: unknown
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001428101.1
Submitted: (May 05, 2020)
Evidence details
Publications
PubMed (1)
Uncertain significance
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808637.1
Submitted: (Aug 24, 2021)
Evidence details
Uncertain significance
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971371.1
Submitted: (Sep 21, 2021)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. Masingue M Mitochondrion 2019 PMID: 29474836
Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease. Papandreou A Journal of inherited metabolic disease 2018 PMID: 30167885
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum. Vasta V Pediatrics international : official journal of the Japan Pediatric Society 2012 PMID: 22494076
Alpers syndrome with mutations in POLG: clinical and investigative features. Hunter MF Pediatric neurology 2011 PMID: 22000311
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. Tang S Journal of medical genetics 2011 PMID: 21880868
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Calvo SE Nature genetics 2010 PMID: 20818383
Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. Kasiviswanathan R The Journal of biological chemistry 2009 PMID: 19478085
Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. Stewart JD Journal of medical genetics 2009 PMID: 19251978
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Wong LJ Human mutation 2008 PMID: 18546365
Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. Ashley N Human molecular genetics 2008 PMID: 18487244
Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. Hakonen AH European journal of human genetics : EJHG 2007 PMID: 17426723
Molecular diagnosis of Alpers syndrome. Nguyen KV Journal of hepatology 2006 PMID: 16545482

Text-mined citations for rs144500145...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021