VCV000206537.86 - ClinVar

NM_002693.3(POLG):c.2890C>T (p.Arg964Cys)

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.

(21)

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.

Conflicting classifications of pathogenicity
Pathogenic(6); Likely pathogenic(4); Uncertain significance(8)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002693.3(POLG):c.2890C>T (p.Arg964Cys)

Variation ID: 206537 Accession: VCV000206537.86

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 89320857 (GRCh38) [ NCBI UCSC ] 15: 89864088 (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	May 25, 2017	Jan 13, 2025	Nov 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002693.3:c.2890C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002684.1:p.Arg964Cys	missense
NM_001126131.2:c.2890C>T	NP_001119603.1:p.Arg964Cys	missense
NC_000015.10:g.89320857G>A
NC_000015.9:g.89864088G>A
NG_008218.2:g.18939C>T
LRG_765:g.18939C>T
LRG_765t1:c.2890C>T	LRG_765p1:p.Arg964Cys

... more HGVS ... less HGVS

Protein change

R964C

Other names

p.R964C:CGC>TGC
p.Arg964Cys

Canonical SPDI

NC_000015.10:89320856: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.

0.00300 (A)

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

The Genome Aggregation Database (gnomAD) 0.00033

Trans-Omics for Precision Medicine (TOPMed) 0.00037

The Genome Aggregation Database (gnomAD), exomes 0.00068

Exome Aggregation Consortium (ExAC) 0.00071

1000 Genomes Project 30x 0.00234

1000 Genomes Project 0.00300

Links

ClinGen: CA316719 dbSNP: rs201477273 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	2020	3033

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	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Nov 13, 2024	RCV000188591.49
Mitochondrial DNA depletion syndrome 4b Progressive sclerosing poliodystrophy	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 18, 2016	RCV000490261.9
Progressive sclerosing poliodystrophy	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 11, 2023	RCV000633558.24
Spinocerebellar atrophy	Pathogenic (1)	no assertion criteria provided	Feb 28, 2019	RCV000984890.9
Mitochondrial DNA depletion syndrome 4b	Pathogenic (1)	criteria provided, single submitter	Jan 3, 2022	RCV001808469.8
Hereditary spastic paraplegia	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2017	RCV001847830.10
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 28, 2024	RCV002247604.10
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Oct 1, 2024	RCV002317145.10
MELAS syndrome	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003232987.9
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2024	RCV003992217.1
POLG-related disorder	Uncertain significance (1)	no assertion criteria provided	Sep 10, 2024	RCV004732762.1
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	Likely pathogenic (1)	criteria provided, single submitter	-	RCV004796080.1
click to load more click to collapse

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.
Likely pathogenic (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Progressive sclerosing poliodystrophy Mitochondrial DNA depletion syndrome 4b Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267455.1 First in ClinVar: May 25, 2017 Last updated: May 25, 2017	Publications: PubMed (3) PubMed: 17436221‚ 19364868‚ 20176107 Number of individuals with the variant: 3 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Uncertain significance (Nov 13, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242214.17 First in ClinVar: Aug 07, 2015 Last updated: Nov 24, 2024	Comment: Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional … (more) Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); 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: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365) (less)
Uncertain significance (Oct 09, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000344604.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (5) PubMed: 17436221‚ 18546365‚ 19762913‚ 21880868‚ 24091540 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG Number of individuals with the variant: 3 Zygosity: Single Heterozygote Sex: mixed
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: SCV000887118.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018	Publications: PubMed (1) PubMed: 17436221 Comment: The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>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.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Mitochondrial DNA depletion syndrome 4b Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163769.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Uncertain significance (Jul 16, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001474646.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (14) PubMed: 29992832‚ 28958595‚ 30951992‚ 32502631‚ 31655921‚ 32348839‚ 25462018‚ 17436221‚ 19364868‚ 20176107‚ 24091540‚ 19762913‚ 21880868‚ 19887119
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial DNA depletion syndrome 4b Affected status: yes Allele origin: germline	3billion Accession: SCV002058398.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:17436221 PMID:17436221 PMID:21880868 PMID:21880868 PMID:19364868 PMID:19364868 PMID:19762913 PMID:19762913 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Areflexia (present) , Episodic hypoventilation (present) , Gastroesophageal reflux (present) , Generalized hypotonia (present) , Status epilepticus (present) , Apnea (present) , Diarrhea (present) , … (more) Areflexia (present) , Episodic hypoventilation (present) , Gastroesophageal reflux (present) , Generalized hypotonia (present) , Status epilepticus (present) , Apnea (present) , Diarrhea (present) , Fever (present) , Hypointensity of cerebral white matter on MRI (present) (less) Zygosity: Single Heterozygote
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: SCV002105577.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Likely pathogenic (Dec 01, 2016)	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: SCV001149560.28 First in ClinVar: Feb 03, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 1
Uncertain significance (Oct 01, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000849456.5 First in ClinVar: Nov 08, 2018 Last updated: Jan 13, 2025	Publications: PubMed (6) PubMed: 17436221‚ 18546365‚ 19364868‚ 19762913‚ 21880868‚ 24091540 Comment: The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide … (more) The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MELAS syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Pediatric Department, Xiangya Hospital, Central South University Accession: SCV002761223.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: This variant was observed in compound heterozygosity with variant (c.2584G>A) Clinical Features: Seizure (present) , Abnormality of the liver (present) , Stroke-like episode (present) Zygosity: Compound Heterozygote
Pathogenic (Mar 30, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519195.2 First in ClinVar: May 28, 2022 Last updated: Apr 01, 2023
Uncertain significance (May 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205903.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Jun 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004227455.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (24) PubMed: 17436221‚ 18546365‚ 19010300‚ 19364868‚ 19762913‚ 19887119‚ 20176107‚ 21880868‚ 23250882‚ 23419467‚ 24091540‚ 25462018‚ 25852747‚ 27917773‚ 28756246‚ 28958595‚ 29214156‚ 29992832‚ 30941926‚ 30951992‚ 32165824‚ 32348839‚ 32502631‚ 35598585 Comment: BS1, PP3, PM3, PS3 Number of individuals with the variant: 3
Uncertain significance (Mar 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003809215.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004812121.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: Criteria applied: PM3_VSTR,PS3_MOD,PP3 Clinical Features: Polyneuropathy (present) Sex: female
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive sclerosing poliodystrophy Mitochondrial DNA depletion syndrome 4b Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005417341.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM3_VeryStrong+PP4+PS3+BS1
Uncertain significance (Oct 28, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002571903.2 First in ClinVar: Sep 17, 2022 Last updated: Dec 14, 2024	Publications: PubMed (9) PubMed: 21880868‚ 18546365‚ 32348839‚ 19364868‚ 31665838‚ 34690748‚ 24091540‚ 19762913‚ 17436221 Comment: Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the … (more) Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, 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 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
Pathogenic (Feb 28, 2019)	no assertion criteria provided Method: provider interpretation	Spinocerebellar atrophy Affected status: yes Allele origin: germline	Codex Genetics Limited Accession: SCV000996001.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020	Publications: PubMed (7) PubMed: 20176107‚ 19364868‚ 19762913‚ 24091540‚ 18546365‚ 21880868‚ 28492532 Age: 30-39 years Sex: female
Uncertain significance (Sep 10, 2024)	no assertion criteria provided Method: clinical testing	POLG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350463.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations … (more) The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain. (less)
Benign (Feb 01, 2024)	Flagged submission flagged submission (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Progressive sclerosing poliodystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000754804.8 First in ClinVar: May 28, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Reported previously in a 2 year old child with hypotonia and ataxia in whom a second POLG variant was not detected (PMID: 18546365); Published functional studies demonstrate that R964C polymerase gamma showed reduced activity in vitro compared to wild-type (PMID: 17436221, 27987238); 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: 19364868, 20176107, 25852747, 20206271, 25462018, 19762913, 27987238, 29992832, 30941926, 31180159, 31521625, 31665838, 32165824, 32005694, 33763395, 33300680, 35314707, 35598585, 34426522, 24091540, 21880868, 17436221, 37470284, 37453004, 18546365)

Comment:

The NM_002693.2:c.2890C>T (NP_002684.1:p.Arg964Cys) [GRCH38: NC_000015.10:g.89320857G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17436221 . 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. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206537, PMID:17436221, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21880868, 19762913, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 17436221, 19364868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 4B (MNGIE type) (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The p.R964C variant (also known as c.2890C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2890. The arginine at codon 964 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two individuals who were compound heterozygotes for POLG alterations and had a clinical diagnosis of an autosomal recessive POLG-related disorder. One individual was an 8-year-old male diagnosed with mtDNA depletion syndrome, mitochondrial recessive ataxia syndrome, and progressive external ophthalmoplegia (PEO) (Ohba C et al. Neurogenetics. 2013 Nov;14(3-4):225-32). The other individual was a 17-year-old male diagnosed with ataxia neuropathy spectrum (ANS), in addition to cerebellar atrophy, and spinocerebellar ataxia with epilepsy (SCAE) (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). The alteration is location in the polymerase domain and functional studies indicated that there was a decrease in the polymerase activity compared to wild type (Yamanaka H et al. J. Infect. Dis., 2007 May;195:1419-25; Bailey CM et al. Antimicrob. Agents Chemother., 2009 Jun;53:2610-2). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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 available evidence, the clinical significance of this variant remains unclear for autosomal recessive POLG-related mitochondrial disorders; however, it is unlikely to be causative of autosomal dominant POLG-related progressive external ophthalmoplegia.

Comment:

Variant summary: POLG c.2890C>T (p.Arg964Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, 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 0.00068 in 251154 control chromosomes, predominantly at a frequency of 0.0088 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders phenotype. c.2890C>T has been reported in the literature in several individuals affected with clinical features of POLG-Related Spectrum Disorders without strong evidence for causality (example, Yamanaka_2007, Wong_2008, Strickler_2009, Tang_2011, Ohba_2013, Han_2019, Hu_2020, Li_2021). These report(s) do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 14% of normal polymerase gamma enzyme activity in vitro (example, Yamanaka_2007). The following publications have been ascertained in the context of this evaluation (PMID: 19364868, 31665838, 32348839, 34690748, 24091540, 19762913, 21880868, 18546365, 17436221). ClinVar contains an entry for this variant (Variation ID: 206537). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Comment:

The POLG c.2890C>T variant is predicted to result in the amino acid substitution p.Arg964Cys. This variant has been documented in patients with variable clinical manifestations including Parkinson disease (Hsieh et al. 2019. PubMed ID: 30941926; Kasahara et al. 2017. PubMed ID: 27987238). An in vitro study suggested that this variant may decrease nucleoside analog discrimination and impair the polymerase activity (Bailey et al. 2009. PubMed ID: 19364868). However, this variant has an allele frequency of 0.93% in Eastern Asians, including one homozygote in a large public population database, which may be too frequent to be a primary cause of disease. This variant has also been listed with conflicting interpretations from pathogenic to benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/206537/). Although we suspect that this variant may be benign, at this time, we cannot rule out the possibility that this variant may function as a hypomorphic allele, and therefore the clinical significance of this variant is currently classified as uncertain.

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
Phenotype-Genotype Analysis Based on Molecular Classification in 135 Children With Mitochondrial Disease.	Wu T	Pediatric neurology	2022	PMID: 35598585
Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers' Syndrome Genotypes.	Li H	Frontiers in pharmacology	2021	PMID: 34690748
High rate of hypertension in patients with m.3243A>G MELAS mutations and POLG variants.	Pauls AD	Mitochondrion	2020	PMID: 32502631
Clinical and molecular characterization of pediatric mitochondrial disorders in south of China.	Hu C	European journal of medical genetics	2020	PMID: 32348839
Copy number variations and multiallelic variants in Korean patients with Leber congenital amaurosis.	Surl D	Molecular vision	2020	PMID: 32165824
Infectious stress triggers a POLG-related mitochondrial disease.	Gaudó P	Neurogenetics	2020	PMID: 31655921
[Clinical and genetic characteristics of 62 children with mitochondrial epilepsy].	Han XD	Zhonghua er ke za zhi = Chinese journal of pediatrics	2019	PMID: 31665838
A unique Japanese CPEO family with a novel homozygous m.14819 T > G (p. S25A) substitution.	Nomura E	Journal of the neurological sciences	2019	PMID: 30951992
POLG R964C and GBA L444P mutations in familial Parkinson's disease: Case report and literature review.	Hsieh PC	Brain and behavior	2019	PMID: 30941926
Identification of the first homozygous POLG mutation causing non-syndromic ovarian dysfunction.	Chen B	Climacteric : the journal of the International Menopause Society	2018	PMID: 29992832
Off-Target Effects of Drugs that Disrupt Human Mitochondrial DNA Maintenance.	Young MJ	Frontiers in molecular biosciences	2017	PMID: 29214156
The mtDNA replication-related genes TFAM and POLG are associated with leprosy in Han Chinese from Southwest China.	Wang D	Journal of dermatological science	2017	PMID: 28958595
Inherited mitochondrial genomic instability and chemical exposures.	Chan SSL	Toxicology	2017	PMID: 28756246
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
Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa.	Ojwach DB	South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde	2016	PMID: 27917773
DNA polymerase γ and disease: what we have learned from yeast.	Lodi T	Frontiers in genetics	2015	PMID: 25852747
Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.	Baruffini E	Mitochondrion	2015	PMID: 25462018
Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood.	Ohba C	Neurogenetics	2013	PMID: 24091540
Alpers-Huttenlocher syndrome.	Saneto RP	Pediatric neurology	2013	PMID: 23419467
What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?	Neeve VC	Brain : a journal of neurology	2012	PMID: 23250882
Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.	Tang S	Journal of medical genetics	2011	PMID: 21880868
Purification and functional characterization of human mitochondrial DNA polymerase gamma harboring disease mutations.	Kasiviswanathan R	Methods (San Diego, Calif.)	2010	PMID: 20176107
Construction and validation of a yeast model system for studying in vivo the susceptibility to nucleoside analogues of DNA polymerase gamma allelic variants.	Baruffini E	Mitochondrion	2010	PMID: 19887119
A variable neurodegenerative phenotype with polymerase gamma mutation.	Stricker S	Journal of neurology, neurosurgery, and psychiatry	2009	PMID: 19762913
R964C mutation of DNA polymerase gamma imparts increased stavudine toxicity by decreasing nucleoside analog discrimination and impairing polymerase activity.	Bailey CM	Antimicrobial agents and chemotherapy	2009	PMID: 19364868
DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations.	Chan SS	Biochimica et biophysica acta	2009	PMID: 19010300
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.	Wong LJ	Human mutation	2008	PMID: 18546365
Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment.	Yamanaka H	The Journal of infectious diseases	2007	PMID: 17436221
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG	-	-	-	-
click to load more click to collapse

Text-mined citations for rs201477273 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_002693.3(POLG):c.2890C>T (p.Arg964Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201477273 ...