VCV000206528.48 - ClinVar

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

Germline

Classification

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.

(14)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_002693.2(POLG):c.[2554C>T];[32G>A]

Identifiers

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

Variation ID: 206528 Accession: VCV000206528.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 89321780 (GRCh38) [ NCBI UCSC ] 15: 89865011 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jan 7, 2017	Oct 20, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002693.3:c.2554C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002684.1:p.Arg852Cys	missense
NM_001126131.2:c.2554C>T	NP_001119603.1:p.Arg852Cys	missense
NC_000015.10:g.89321780G>A
NC_000015.9:g.89865011G>A
NG_008218.2:g.18016C>T
LRG_765:g.18016C>T
LRG_765t1:c.2554C>T	LRG_765p1:p.Arg852Cys

... more HGVS ... less HGVS

Protein change

R852C

Other names

p.R852C:CGC>TGC

Canonical SPDI

NC_000015.10:89321779:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00005

The Genome Aggregation Database (gnomAD) 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00008

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA316701 dbSNP: rs144500145 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
POLG		-	-	GRCh38 GRCh37	1868	3010

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2023	RCV000188581.38
Progressive sclerosing poliodystrophy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000633537.10
Mitochondrial DNA depletion syndrome 1 Mitochondrial DNA depletion syndrome 4b Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Progressive sclerosing poliodystrophy Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762953.3
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001252349.3
Hereditary spastic paraplegia	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2017	RCV001847829.4
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	May 31, 2022	RCV002517007.3
POLG-Related Spectrum Disorders	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2024	RCV004526636.2

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 Help 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 Help 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 Help 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.
Pathogenic (Aug 02, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610294.1 First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017
Pathogenic (Oct 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine Accession: SCV000886909.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Publications: PubMed (1) PubMed: 16545482 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) 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 reported in PMID:16545482 . 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)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive sclerosing poliodystrophy Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Mitochondrial DNA depletion syndrome 1 Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Mitochondrial DNA depletion syndrome 4b Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893385.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242203.15 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	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) 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20818383, 23545419, 17426723, 24985751, 27538604, 29474836, 18546365, 16545482, 19478085, 19251978, 30167885, 24642831, 32445240, 32964447) (less)
Pathogenic (Mar 02, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001145154.3 First in ClinVar: Jan 19, 2020 Last updated: Jan 26, 2024	Publications: PubMed (19) PubMed: 30167885‚ 29474836‚ 16545482‚ 17426723‚ 18546365‚ 19251978‚ 19478085‚ 32445240‚ 20818383‚ 34052969‚ 19862739‚ 21259344‚ 21484424‚ 22494076‚ 23084792‚ 31085725‚ 32964447‚ 22000311‚ 21880868 Comment: The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been … (more) The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in individuals with autosomal recessive POLG-related disorders. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19478085) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure. (less)
Pathogenic (Dec 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000754783.6 First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 28492532‚ 16545482‚ 18546365‚ 21880868‚ 22000311‚ 19478085 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 852 of the POLG protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 852 of the POLG protein (p.Arg852Cys). This variant is present in population databases (rs144500145, gnomAD 0.01%). This missense change has been observed in individual(s) with Alpers syndrome, and ataxia neuropathy spectrum (PMID: 16545482, 18546365, 21880868, 22000311; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206528). 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: 19478085). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001149562.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: POLG: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting Number of individuals with the variant: 2
Pathogenic (Dec 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002105572.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Pathogenic (May 31, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003681268.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 16545482‚ 19478085‚ 22000311‚ 30167885‚ 32964447 Comment: 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 … (more) 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; Stödberg, 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. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205849.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	POLG-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005039126.2 First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024	Publications: PubMed (5) PubMed: 18546365‚ 16545482‚ 19478085‚ 22000311‚ 30167885 Comment: Variant summary: POLG c.2554C>T (p.Arg852Cys) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein … (more) Variant summary: POLG c.2554C>T (p.Arg852Cys) 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 4.8e-05 in 251398 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. c.2554C>T has been reported in the literature in the compound heterozygous state in individuals affected with POLG-Related Spectrum Disorders (e.g. Nguyen_2006, Wong_2008, Hunter_2011, Papandreou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <10% of normal activity (Kasiviswanathan_2009). The following publications have been ascertained in the context of this evaluation (PMID: 22000311, 19478085, 16545482, 30167885, 18546365). ClinVar contains an entry for this variant (Variation ID: 206528). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Uncertain significance (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001428101.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808637.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes 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 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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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 reported in PMID:16545482 . 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.

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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20818383, 23545419, 17426723, 24985751, 27538604, 29474836, 18546365, 16545482, 19478085, 19251978, 30167885, 24642831, 32445240, 32964447)

Comment:

The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in individuals with autosomal recessive POLG-related disorders. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19478085) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 852 of the POLG protein (p.Arg852Cys). This variant is present in population databases (rs144500145, gnomAD 0.01%). This missense change has been observed in individual(s) with Alpers syndrome, and ataxia neuropathy spectrum (PMID: 16545482, 18546365, 21880868, 22000311; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 206528). 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: 19478085). For these reasons, this variant has been classified as Pathogenic.

Comment:

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; Stödberg, 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.

Comment:

Variant summary: POLG c.2554C>T (p.Arg852Cys) 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 4.8e-05 in 251398 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. c.2554C>T has been reported in the literature in the compound heterozygous state in individuals affected with POLG-Related Spectrum Disorders (e.g. Nguyen_2006, Wong_2008, Hunter_2011, Papandreou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in <10% of normal activity (Kasiviswanathan_2009). The following publications have been ascertained in the context of this evaluation (PMID: 22000311, 19478085, 16545482, 30167885, 18546365). ClinVar contains an entry for this variant (Variation ID: 206528). Based on the evidence outlined above, the variant was classified as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic and Clinical Predictors of Ataxia in Pediatric Primary Mitochondrial Disorders.	Martin-Saavedra JS	Cerebellum (London, England)	2022	PMID: 34052969
Epilepsy syndromes, etiologies, and the use of next-generation sequencing in epilepsy presenting in the first 2 years of life: A population-based study.	Stödberg T	Epilepsia	2020	PMID: 32964447
Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations.	Alves CAPF	Annals of neurology	2020	PMID: 32445240
Clinical Reasoning: Refractory status epilepticus in a primigravida.	Shi H	Neurology	2019	PMID: 31085725
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
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
Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.	Blankenberg FG	Molecular genetics and metabolism	2012	PMID: 23084792
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
Complex III staining in blue native polyacrylamide gels.	Smet J	Journal of inherited metabolic disease	2011	PMID: 21484424
Mitochondrial mimicry of multiple system atrophy of the cerebellar subtype.	Mehta AR	Movement disorders : official journal of the Movement Disorder Society	2011	PMID: 21259344
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency.	Calvo SE	Nature genetics	2010	PMID: 20818383
Subcomplexes of mitochondrial complex V reveal mutations in mitochondrial DNA.	Smet J	Electrophoresis	2009	PMID: 19862739
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
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
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Text-mined citations for rs144500145 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144500145 ...