VCV000021318.35 - ClinVar

NM_002693.3(POLG):c.578G>A (p.Arg193Gln)

Germline

Top reviewed classifications are shown here.

Submission summary:

12 submissions

12 submitters

7 conditions

Reviewed by expert panel

Uncertain significance

May 2021 by ClinGen Mitoch… FDA Recognized Database

for Mitochondrial disease

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002693.3(POLG):c.578G>A (p.Arg193Gln)

Variation ID: 21318 Accession: VCV000021318.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q26.1 15: 89333177 (GRCh38) [ NCBI UCSC ] 15: 89876408 (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	Apr 4, 2013	Oct 20, 2024	May 7, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_002693.3:c.578G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002684.1:p.Arg193Gln	missense
NM_001126131.2:c.578G>A	NP_001119603.1:p.Arg193Gln	missense
NC_000015.10:g.89333177C>T
NC_000015.9:g.89876408C>T
NG_008218.2:g.6619G>A
LRG_765:g.6619G>A
LRG_765t1:c.578G>A	LRG_765p1:p.Arg193Gln
	P54098:p.Arg193Gln

... more HGVS ... less HGVS

Protein change

R193Q

Other names

p.R193Q:CGG>CAG
NM_002693.2(POLG):c.578G>A

Canonical SPDI

NC_000015.10:89333176:C:T

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.

0.00060 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00015

Exome Aggregation Consortium (ExAC) 0.00023

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00070

The Genome Aggregation Database (gnomAD) 0.00071

1000 Genomes Project 30x 0.00078

Links

ClinGen: CA241475 UniProtKB: P54098#VAR_019267 dbSNP: rs3176162 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
POLGARF		-	-	GRCh38	-	936

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.
Mitochondrial disease	Uncertain significance (1)	reviewed by expert panel	May 7, 2021	RCV000020482.12
Progressive sclerosing poliodystrophy	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000541557.19
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	May 1, 2024	RCV000724388.27
POLG-Related Spectrum Disorders	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001121514.12
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jan 30, 2019	RCV002313715.9
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	Uncertain significance (1)	criteria provided, single submitter	Nov 9, 2021	RCV002476997.8
POLG-related disorder	Likely benign (1)	no assertion criteria provided	Aug 11, 2023	RCV003985723.2

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.
Uncertain significance (May 07, 2021)	reviewed by expert panel (clingen mito disease acmg specifications v1-1) Method: curation	Mitochondrial disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001994834.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/32aa42c6-6e27-46ba-a061-ce5f93499fbc Comment: The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It … (more) The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It is also seen in the homozygous state in 1 individual in gnomAD (BS2). This variant is not reported in the literature and no computational data is available. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2. (less)
Uncertain significance (Nov 09, 2021)	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: SCV002779724.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Jan 31, 2024)	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: SCV000630159.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024
Uncertain significance (Nov 06, 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: SCV000227268.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	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: 5 Sex: mixed
Likely benign (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: SCV000887102.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Comment: The NM_002693.2:c.578G>A (NP_002684.1:p.Arg193Gln) [GRCH38: NC_000015.10:g.89333177C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets … (more) The NM_002693.2:c.578G>A (NP_002684.1:p.Arg193Gln) [GRCH38: NC_000015.10:g.89333177C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	POLG-Related Spectrum Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001280139.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Jun 05, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001474649.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (1) PubMed: 25462018
Uncertain significance (May 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002541300.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Likely benign (May 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242161.16 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 25462018)
Uncertain significance (Jan 30, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848541.4 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: The p.R193Q variant (also known as c.578G>A), located in coding exon 1 of the POLG gene, results from a G to A substitution at nucleotide … (more) The p.R193Q variant (also known as c.578G>A), located in coding exon 1 of the POLG gene, results from a G to A substitution at nucleotide position 578. The arginine at codon 193 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (May 01, 2024)	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: SCV005051155.5 First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely benign (Aug 11, 2023)	no assertion criteria provided Method: clinical testing	POLG-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004723947.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Comment:

The c.578G>A (p.Arg193Gln) variant in POLG has been reported with an allele frequency in the population at 0.2 % in African Americans in gnomAD. It is also seen in the homozygous state in 1 individual in gnomAD (BS2). This variant is not reported in the literature and no computational data is available. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BS2.

Comment:

The NM_002693.2:c.578G>A (NP_002684.1:p.Arg193Gln) [GRCH38: NC_000015.10:g.89333177C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The p.R193Q variant (also known as c.578G>A), located in coding exon 1 of the POLG gene, results from a G to A substitution at nucleotide position 578. The arginine at codon 193 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.	Baruffini E	Mitochondrion	2015	PMID: 25462018
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/32aa42c6-6e27-46ba-a061-ce5f93499fbc	-	-	-	-

Text-mined citations for rs3176162 ...

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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_002693.3(POLG):c.578G>A (p.Arg193Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3176162 ...