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NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Pathogenic(1);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: May 28, 2021)
Last evaluated:
Sep 18, 2020
Accession:
VCV000206548.7
Variation ID:
206548
Description:
single nucleotide variant
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NM_002693.2(POLG):c.3139C>T (p.Arg1047Trp)

Allele ID
202934
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q26.1
Genomic location
15: 89319065 (GRCh38) GRCh38 UCSC
15: 89862296 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NG_011736.1:g.80103G>A
NC_000015.10:g.89319065G>A
NC_000015.9:g.89862296G>A
... more HGVS
Protein change
R1047W
Other names
p.R1047W:CGG>TGG
Canonical SPDI
NC_000015.10:89319064:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00040 (A)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 0.00040
Links
ClinGen: CA316740
dbSNP: rs181860632
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Nov 24, 2018 RCV000720665.1
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Jun 8, 2020 RCV000188603.9
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Sep 18, 2020 RCV000633548.4
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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
1309 1427

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 19, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000281261.2
Submitted: (Oct 05, 2017)
Evidence details
Likely pathogenic
(Oct 09, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000242226.8
Submitted: (Nov 28, 2017)
Evidence details
Comment:
A variant that is likely pathogenic has been identified in the POLG gene. The R1047W variant has been previously reported in several unrelated patients who … (more)
Uncertain significance
(Sep 20, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000705543.2
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Likely 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: SCV000887120.1
Submitted: (Nov 16, 2018)
Evidence details
Publications
PubMed (1)
Comment:
The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has … (more)
Uncertain significance
(Nov 24, 2018)
criteria provided, single submitter
Method: clinical testing
Seizures
Allele origin: germline
Ambry Genetics
Accession: SCV000851544.2
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The p.R1047W variant (also known as c.3139C>T), located in coding exon 19 of the POLG gene, results from a C to T substitution at nucleotide … (more)
Uncertain significance
(Sep 18, 2020)
criteria provided, single submitter
Method: clinical testing
Progressive sclerosing poliodystrophy
Allele origin: germline
Invitae
Accession: SCV000754794.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces arginine with tryptophan at codon 1047 of the POLG protein (p.Arg1047Trp). The arginine residue is highly conserved and there is a … (more)
Likely pathogenic
(Jun 08, 2020)
criteria provided, single submitter
Method: clinical testing
Not provided
Allele origin: germline
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802079.2
Submitted: (May 28, 2021)
Evidence details
Publications
PubMed (9)
Comment:
PS4_moderate, PM2, PM3, PM5, PP5

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
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Lindy AS Epilepsia 2018 PMID: 29655203
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
Alpers-Huttenlocher syndrome. Saneto RP Pediatric neurology 2013 PMID: 23419467
Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy. Nolte KW Neuropathology : official journal of the Japanese Society of Neuropathology 2013 PMID: 22537151
Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. Lax NZ Brain : a journal of neurology 2012 PMID: 22189570
Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol γ. Euro L Nucleic acids research 2011 PMID: 21824913
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
Juvenile Alpers disease. Wiltshire E Archives of neurology 2008 PMID: 18195149
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG - - - -

Text-mined citations for rs181860632...

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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 Jun 02, 2021