NM_002693.3:c.1174C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_002693.3(POLG):c.1174C>G(p.Leu392Val) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,692 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:9

Conservation

PhyloP100: 4.51

Publications

16 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]

POLG Gene-Disease associations (from GenCC):

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
mitochondrial DNA depletion syndrome 4a
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P
sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P
autosomal dominant progressive external ophthalmoplegia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial neurogastrointestinal encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
recessive mitochondrial ataxia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
spinocerebellar ataxia with epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

POLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002693.3

BP4

Computational evidence support a benign effect (MetaRNN=0.021485358).

BP6

Variant 15-89328532-G-C is Benign according to our data. Variant chr15-89328532-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198151.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.1174C>G	p.Leu392Val	missense_variant	Exon 6 of 23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2 link	c.1174C>G	p.Leu392Val	missense_variant	Exon 6 of 23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.1174C>G	p.Leu392Val	missense_variant	Exon 6 of 23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

275

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00173

AC:

435

AN:

251118

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00782

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.00205

AC:

3002

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1468

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33474

American (AMR)

AF:

0.00110

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00724

AC:

385

AN:

53150

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00222

AC:

2471

AN:

1111834

Other (OTH)

AF:

0.00137

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00181

AC:

275

AN:

152260

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41556

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0108

AC:

115

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00171

AC:

116

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00173

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00161

AC:

195

EpiCase

AF:

0.00207

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

POLG: PM2, BS2 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in 0.1774% (501/282492 alleles) in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18546365, 31669236, 20434700, 25462018, 21880868, 25118206, 17846414, 23251356, 29341116) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 10, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive sclerosing poliodystrophy

Benign:2

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.1174C>G (NP_002684.1:p.Leu392Val) [GRCH38: NC_000015.10:g.89328532G>C] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:20434700 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. 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. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Uncertain:1

Sep 29, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLG-Related Spectrum Disorders

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Inborn genetic diseases

Benign:1

Dec 07, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

POLG-related disorder

Benign:1

Apr 22, 2022

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

0.28

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.021

T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.9

M;M

PhyloP100

4.5

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.041

D;D

Sift4G

Uncertain

0.043

D;D

Polyphen

1.0

D;D

Vest4

0.74

MVP

0.93

MPC

0.66

ClinPred

0.052

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.63

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over