rs150233690

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_002693.3(POLG):c.3131T>C(p.Val1044Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,614,046 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 2 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:1

Conservation

PhyloP100: 1.50

Publications

7 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_002693.3

BP4

Computational evidence support a benign effect (MetaRNN=0.11218697).

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.3131T>C	p.Val1044Ala	missense_variant	Exon 20 of 23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2 link	c.3131T>C	p.Val1044Ala	missense_variant	Exon 20 of 23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.3131T>C	p.Val1044Ala	missense_variant	Exon 20 of 23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000648

AC:

163

AN:

251418

AF XY:

0.000662

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000985

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000832

AC:

1217

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000862

AC XY:

627

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000537

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000719

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000970

AC:

1079

AN:

1112010

Other (OTH)

AF:

0.000546

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000591

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41430

American (AMR)

AF:

0.000458

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68024

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000871

Hom.:

Bravo

AF:

0.000589

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000749

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Jun 26, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in an individual with severe encephalopathy, intractable epilepsy, an athetoid-ataxic movement disorder, and developmental regression, who also harbored a second POLG variant on the opposite allele. Please note that this second POLG variant is classified as benign by GeneDx (PMID: 21357833); Reported previously in a child with developmental delay, hypotonia, encephalopathy, seizure, intractable seizure, muscle weakness, gastrointestinal reflux in whom a second POLG variant was not described (PMID: 21880868); In silico analysis suggests that this missense variant does not alter protein structure/function; Reported previously in a patient with mtDNA depletion syndrome with liver fibrosis and portal hypertension who harbored a second POLG variant (phase unknown) (PMID: 28776642); This variant is associated with the following publications: (PMID: 28337550, 34426522, Singh2021[Poster], 32391929, 21357833, 21880868, 28776642, Betler2024[Review]) -

Sep 04, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2021

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive sclerosing poliodystrophy

Uncertain:1Benign:1

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NM_002693.2:c.3131T>C (NP_002684.1:p.Val1044Ala) [GRCH38: NC_000015.10:g.89319073A>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21357833 . This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Aug 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POLG c.3131T>C (p.Val1044Ala) 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. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders (0.00065 vs 0.0035), allowing no conclusion about variant significance. c.3131T>C has been reported in the literature as a compound heterozygous genotype in an individual with an Alpers-like phenotype (Isohanni_2011), in the heterozygous state together with other POLG variants (phase unspecified) in an individual suspected of an atypical mitochondrial DNA depletion syndrome presenting with liver fibrosis with portal hypertension (Stalke_2018), and as an uninformative genotype (i.e. zygosity not specified) in at least one individual from a cohort of patients with POLG-related disorders (Hkitmat_2020). It has also been reported in a case-control study in two individuals affected with multiple sclerosis, but was also found in one control individual (Traboulsee_2017). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32391929, 21357833, 28776642, 28337550). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS, and one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3131T>C (p.V1044A) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 3131, causing the valine (V) at amino acid position 1044 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Jan 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

POLG-related disorder

Uncertain:1

Jun 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The POLG c.3131T>C variant is predicted to result in the amino acid substitution p.Val1044Ala. This variant has been reported in the compound heterozygous state with another polymorphic variant in a patient with Alpers-like phenotype; however, the pathogenicity of this variant was not established (Isohanni et al. 2011. PubMed ID: 21357833). The c.3131T>C variant was also detected, along with another missense variant and a 5’ UTR variant, in an individual with liver fibrosis with portal hypertension (Stalke et al. 2018. PubMed ID: 28776642). Additionally, this variant was reported in the heterozygous state in a patient who presented with developmental delay, hypotonia, encephalopathy, seizure, and gastrointestinal reflux (Tang et al. 2011. PubMed ID: 21880868), as well as in a cohort of patients who presented with suspected multiple sclerosis (Traboulsee et al. 2017. PubMed ID: 28337550); however, in the latter study, this variant was also identified in an unaffected control. This variant is reported in 0.088% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C3150914:Mitochondrial DNA depletion syndrome 4b

Uncertain:1

May 27, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Early-onset Parkinson disease 20

Uncertain:1

Oct 15, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EEG abnormality

Uncertain:1

Dec 22, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.060

CADD

Benign

9.6

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.67

D;D

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.44

.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.0

L;L

PhyloP100

1.5

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.61

Sift

Benign

0.44

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0080

B;B

Vest4

0.39

MVP

0.86

MPC

0.20

ClinPred

0.0062

GERP RS

0.072

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.54

Mutation Taster

=12/88

disease causing

(source)

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

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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