ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.3287G>A (p.Arg1096His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(4); Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.3287G>A (p.Arg1096His)
Variation ID: 206557 Accession: VCV000206557.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89318736 (GRCh38) [ NCBI UCSC ] 15: 89861967 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 May 1, 2024 Jan 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.3287G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Arg1096His missense NM_001126131.2:c.3287G>A NP_001119603.1:p.Arg1096His missense NC_000015.10:g.89318736C>T NC_000015.9:g.89861967C>T NG_008218.2:g.21060G>A NG_011736.1:g.79774C>T LRG_500:g.79774C>T LRG_765:g.21060G>A LRG_765t1:c.3287G>A LRG_765p1:p.Arg1096His P54098:p.Arg1096His - Protein change
- R1096H
- Other names
- p.R1096H:CGT>CAT
- Canonical SPDI
- NC_000015.10:89318735:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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POLG | - | - |
GRCh38 GRCh37 |
1 | 2962 | |
POLGARF | - | - | GRCh38 | - | 2918 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 10, 2021 | RCV000188614.17 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 14, 2024 | RCV000551933.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2017 | RCV002314742.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV003479051.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Feb 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000706349.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Sex: mixed
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Likely pathogenic
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205855.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000887124.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
The NM_002693.2:c.3287G>A (NP_002684.1:p.Arg1096His) [GRCH38: NC_000015.10:g.89318736C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the … (more)
The NM_002693.2:c.3287G>A (NP_002684.1:p.Arg1096His) [GRCH38: NC_000015.10:g.89318736C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. (less)
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Pathogenic
(Nov 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000242237.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (Stumpf et al., 2010; Sohl et al., 2013); Not observed at a significant frequency in large population cohorts … (more)
Published functional studies demonstrate a damaging effect (Stumpf et al., 2010; Sohl et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23430834, 23873972, 17280874, 24265579, 23208208, 20185557, 19752458, 23077218, 21880868, 22189570, 20843780, 21305355, 20803511, 23545419, 12707443, 29025585, 22176657, 34288125, 34690748, 25129007, 25340760, 32347949, 16621917, 33046616) (less)
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Pathogenic
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004222831.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: POLG c.3287G>A (p.Arg1096His) results in a non-conservative amino acid change located in the palm domain (IPR001098) of the encoded protein sequence. Five of … (more)
Variant summary: POLG c.3287G>A (p.Arg1096His) results in a non-conservative amino acid change located in the palm domain (IPR001098) 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 2e-05 in 251306 control chromosomes (i.e., 5 heterozygotes; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3287G>A has been reported in the literature in multiple compound heterozygous individuals as well as at least one homozygote affected with POLG-Related Spectrum Disorders (e.g., Horvath_2006, Schulte_2009, Savard_2013, Bijarnia-Mahay_2014, Hou_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16621917, 35289132, 19752458, 23873972, 25129007). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000630143.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1096 of the POLG protein (p.Arg1096His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1096 of the POLG protein (p.Arg1096His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive Alpers syndrome or progressive external ophthalmoplegia (PMID: 16621917, 19752458, 35289132). ClinVar contains an entry for this variant (Variation ID: 206557). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557, 23208208). This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707443, 21305355, 21880868, 22189570, 23545419, 24265579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000848987.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The p.R1096H variant (also known as c.3287G>A), located in coding exon 20 of the POLG gene, results from a G to A substitution at nucleotide … (more)
The p.R1096H variant (also known as c.3287G>A), located in coding exon 20 of the POLG gene, results from a G to A substitution at nucleotide position 3287. The arginine at codon 1096 is replaced by histidine, an amino acid with highly similar properties. In one functional study, this alteration's yeast equivalent was found to cause high mytocondrial dysfunction and decreased polymerase activity leading to mtDNA depletion (Stumpf JD et al. Hum. Mol. Genet., 2010 Jun;19:2123-33). In another functional study, this alteration showed decreased affinity for the DNA substrate and decreased rate of nucleotide incorporation, but increased affinity for the incoming nucleotide (Sohl CD et al. Hum. Mol. Genet., 2013 Mar;22:1074-85). In addition, this alteration has been detected in conjunction with POLG p.R627Q in several individuals with phenotypes including: Alpers syndrome, progressive external ophthalmoplegia (PEO), focal nocturnal motor epilepsy with status epilepticus at one month postpartum, and early-onset cerebellar ataxia with PEO; however, phase was not determined in any of these individuals (Horvath R et al. Brain, 2006 Jul;129:1674-84; Schulte C et al. Neurology, 2009 Sep;73:898-900; Savard M et al. Neurology, 2013 Aug;81:770-1; Schicks J et al. Mov. Disord., 2010 Nov;25:2678-82).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel and recurrent nuclear gene variations in a cohort of Chinese progressive external ophthalmoplegia patients with multiple mtDNA deletions. | Hou Y | Molecular genetics & genomic medicine | 2022 | PMID: 35289132 |
Mitochondrial DNA depletion syndrome causing liver failure. | Bijarnia-Mahay S | Indian pediatrics | 2014 | PMID: 25129007 |
Propofol-related infusion syndrome heralding a mitochondrial disease: case report. | Savard M | Neurology | 2013 | PMID: 23873972 |
Clinical and molecular features of POLG-related mitochondrial disease. | Stumpf JD | Cold Spring Harbor perspectives in biology | 2013 | PMID: 23545419 |
Mutations in human DNA polymerase γ confer unique mechanisms of catalytic deficiency that mirror the disease severity in mitochondrial disorder patients. | Sohl CD | Human molecular genetics | 2013 | PMID: 23208208 |
Universal heteroplasmy of human mitochondrial DNA. | Payne BA | Human molecular genetics | 2013 | PMID: 23077218 |
A novel POLG gene mutation in a patient with SANDO. | Kurt B | Journal of experimental and integrative medicine | 2012 | PMID: 24265579 |
Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. | Lax NZ | Brain : a journal of neurology | 2012 | PMID: 22189570 |
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. | Tang S | Journal of medical genetics | 2011 | PMID: 21880868 |
Gender variability in presentation with Alpers' syndrome: a report of eight patients from the UAE. | Mohamed K | Journal of inherited metabolic disease | 2011 | PMID: 21305355 |
Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing. | Wang W | Nucleic acids research | 2011 | PMID: 20843780 |
POLG, but not PEO1, is a frequent cause of cerebellar ataxia in Central Europe. | Schicks J | Movement disorders : official journal of the Movement Disorder Society | 2010 | PMID: 20803511 |
mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae. | Stumpf JD | Human molecular genetics | 2010 | PMID: 20185557 |
Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations. | Schulte C | Neurology | 2009 | PMID: 19752458 |
Depletion of mtDNA: syndromes and genes. | Alberio S | Mitochondrion | 2007 | PMID: 17280874 |
Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. | Horvath R | Brain : a journal of neurology | 2006 | PMID: 16621917 |
Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). | Agostino A | Neurology | 2003 | PMID: 12707443 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs368435864 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.