NM_002693.3:c.578G>A

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA241475/MONDO:0044970/014

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

3
16

Clinical Significance

Uncertain significance reviewed by expert panel U:8B:4

Conservation

PhyloP100: 0.369

Publications

8 publications found
Variant links:
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -4 ACMG points.

BS2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.578G>A p.Arg193Gln missense_variant Exon 2 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.578G>A p.Arg193Gln missense_variant Exon 2 of 23 NP_001119603.1 P54098E5KNU5
POLGARFNM_001430120.1 linkc.633G>A p.Ala211Ala synonymous_variant Exon 1 of 2 NP_001417049.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.578G>A p.Arg193Gln missense_variant Exon 2 of 23 1 NM_002693.3 ENSP00000268124.5 P54098
POLGARFENST00000706918.1 linkc.633G>A p.Ala211Ala synonymous_variant Exon 1 of 2 ENSP00000516626.1 A0A3B3IS91

Frequencies

GnomAD3 genomes
AF:
0.000663
AC:
101
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00236
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000955
GnomAD2 exomes
AF:
0.000151
AC:
32
AN:
211358
AF XY:
0.0000954
show subpopulations
Gnomad AFR exome
AF:
0.00183
Gnomad AMR exome
AF:
0.000139
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000195
GnomAD4 exome
AF:
0.0000503
AC:
71
AN:
1412880
Hom.:
0
Cov.:
32
AF XY:
0.0000345
AC XY:
24
AN XY:
696658
show subpopulations
African (AFR)
AF:
0.00182
AC:
58
AN:
31938
American (AMR)
AF:
0.000104
AC:
4
AN:
38514
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23508
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38950
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80590
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50740
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5564
European-Non Finnish (NFE)
AF:
0.00000184
AC:
2
AN:
1084962
Other (OTH)
AF:
0.000120
AC:
7
AN:
58114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
4
9
13
18
22
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000663
AC:
101
AN:
152346
Hom.:
0
Cov.:
33
AF XY:
0.000497
AC XY:
37
AN XY:
74498
show subpopulations
African (AFR)
AF:
0.00236
AC:
98
AN:
41584
American (AMR)
AF:
0.00
AC:
0
AN:
15312
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.000945
AC:
2
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000104
Hom.:
0
Bravo
AF:
0.000699
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000207
AC:
25
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8Benign:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:1
May 18, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25462018) -

May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 21, 2023
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental analysis yielded inconclusive results regarding the impact of this variant on protein function. The effect of variant in mtDNA mutability was shown to be neutral in a yeast model (PMID 25462018). However, this has not been studied in a mammalian model system. -

May 21, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 06, 2017
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Progressive sclerosing poliodystrophy Benign:2
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 01, 2018
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1
Nov 09, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

POLG-Related Spectrum Disorders Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Inborn genetic diseases Uncertain:1
Jan 30, 2019
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Mitochondrial disease Uncertain:1
May 07, 2021
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Significance:Uncertain significance
Review Status:reviewed by expert panel
Collection Method:curation

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. -

POLG-related disorder Benign:1
Aug 11, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.19
T;T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.72
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.010
T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.3
L;L
PhyloP100
0.37
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
0.76
N;N
REVEL
Benign
0.16
Sift
Benign
0.42
T;T
Sift4G
Benign
0.39
T;T
Polyphen
0.019
B;B
Vest4
0.089
MVP
0.76
MPC
0.18
ClinPred
0.014
T
GERP RS
2.6
PromoterAI
0.056
Neutral
Varity_R
0.074
gMVP
0.41
Mutation Taster
=97/3
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs3176162; hg19: chr15-89876408; COSMIC: COSV51521834; COSMIC: COSV51521834; API