rs3176162

Positions:

chr15-89333177-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -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

Clinical Significance

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

Conservation

PhyloP100: 0.369

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]

POLG links:

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]

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -4 ACMG points.

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.633G>A	p.Ala211=	synonymous_variant	2/23
POLG	NM_001126131.2 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1 linkuse as main transcript	c.633G>A	p.Ala211=	synonymous_variant	1/2			P1

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152228

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.000151

AC:

AN:

211358

Hom.:

AF XY:

0.0000954

AC XY:

AN XY:

115318

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 SAS 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:

AN:

1412880

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

696658

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.000104

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000184

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.000663

AC:

101

AN:

152346

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.0000860

Hom.:

Bravo

AF:

0.000699

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000207

AC:

Asia WGS

AF:

0.000289

AC:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	This variant is associated with the following publications: (PMID: 25462018) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	- -

Progressive sclerosing poliodystrophy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

POLG-Related Spectrum Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2019

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

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 07, 2021

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 11, 2023

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

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.88

.;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

0.69

N;N

PrimateAI

Uncertain

0.51

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

GERP RS

2.6

Varity_R

0.074

gMVP

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over