rs202037973

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_002693.3(POLG):c.2246T>C(p.Phe749Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1

Conservation

PhyloP100: 7.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

PP5

Variant 15-89323423-A-G is Pathogenic according to our data. Variant chr15-89323423-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.2246T>C	p.Phe749Ser	missense_variant	Exon 13 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.2246T>C	p.Phe749Ser	missense_variant	Exon 13 of 23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.2246T>C	p.Phe749Ser	missense_variant	Exon 13 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251288

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1460476

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.000957

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000243

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000516

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 749 of the POLG protein (p.Phe749Ser). This variant is present in population databases (rs202037973, gnomAD 0.07%). This missense change has been observed in individuals with Alpers syndrome, autosomal recessive progressive external ophthalmoplegia, and/or seizures (PMID: 16545482, 18716558, 21670405, 21880868, 28865037). ClinVar contains an entry for this variant (Variation ID: 206520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.2246T>C (NP_002684.1:p.Phe749Ser) [GRCH38: NC_000015.10:g.89323423A>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -

POLG-Related Spectrum Disorders

Pathogenic:3

Mar 25, 2022

DASA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2246T>C;p.(Phe749Ser) missense change has been observed in affected individual(s) PMID: 24642831; PMID: 21880868; PMID: 21670405)-PS4_moderate. The variant is present at low allele frequencies population databases (rs202037973 – gnomAD 0.0006368%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Phe749Ser) was detected in trans with a pathogenic variant (PMID: 21880868; PMID: 21670405) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic -

Apr 26, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.2246T>C (p.Phe749Ser) variant is a missense variant that has been reported in four studies, in which it is found in a compound heterozygous state in a total of six individuals, including in three with POLG deficiency, in one with autosomal recessive POLG-related disorders, in one with Alpers syndrome, and in one with some features of the Alpers-Huttenlocher syndrome (Nguyen et al. 2006; Zsurka et al. 2008; Milone et al. 2011; Tang et al. 2011). The p.Phe749Ser variant was absent from 100 control subjects and is reported at a frequency of 0.000681 in the African population of the Genome Aggregation Database. The p.Phe749Ser variant demonstrated reduced mitochondrial DNA copy numbers in patient blood and tissue samples (Zsurka et al. 2008). Muscle biopsies from the Alpers-Huttenlocher syndrome patient revealed large mtDNA deletions, however, the mitochondrial impairment in the muscle tissue could not be explained solely by deletions (Zsurka et al. 2008). The phe749 residue is in the linker region suggested to be involved in proteinâ€“protein interactions but is not critical for catalytic function of the enzyme (Euro et al. 2011). Based on the collective evidence, the p.Phe749Ser variant is classified as likely pathogenic for POLG-related spectrum disorders. -

Mar 15, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLG c.2246T>C (p.Phe749Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251288 control chromosomes. c.2246T>C has been reported in the literature in multiple compound heterozygous individuals carrying additional pathogenic variants affected with clinical features of POLG-related disorders (examples: Tang_2011, Milone_2011, Zsurka_2008), including reduced mitochondrial enzyme activity (Zsurska_2008), and in Alpers syndrome (examples: Hikmat_2017, Nguyen_2006). These data indicate that the variant is very likely to be associated with disease. Two publications report predictive evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (examples: Euro_2011, Zsurska_2008). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=2), likely pathogenic (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:2Uncertain:1

Feb 25, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2020

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Aug 05, 2024

GeneDx

Significance: Likely pathogenic

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; This variant is associated with the following publications: (PMID: 17538929, 21824913, 23446635, 32347949, 34777884, 21670405, 17280874, 21880868, 16545482, 18716558, 21953457, 19195941, 24642831, Alghtani_Article, 28206745, 35289132, 36510129, 38845467, 32391929, 17682973) -

Inborn genetic diseases

Pathogenic:1

Aug 12, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2246T>C (p.F749S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 2246, causing the phenylalanine (F) at amino acid position 749 to be replaced by a serine (S). Based on the supporting evidence, this alteration is classified as likely pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the C allele has an overall frequency of 0.01% (18/282674) total alleles studied. The highest observed frequency was 0.07% (17/24960) of African alleles. This alteration has been identified in the compound heterozygous state in individuals exhibiting a range a phenotypes associated with autosomal recessive POLG-related mitochondrial disorders (Milone, 2011; Nguyen, 2006; Tang, 2011; Zsurka, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b

Pathogenic:1

Jan 28, 2022

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLG-related disorder

Pathogenic:1

Jun 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.2246T>C variant is predicted to result in the amino acid substitution p.Phe749Ser. This variant has previously been reported in the compound heterozygous state in patients who presented with POLG-associated disorders, including Alpers syndrome, progressive external ophthalmoplegia (PEO), and intractable seizures (Nguyen et al. 2006. PubMed ID: 16545482; Zsurka et al. 2008. PubMed ID: 18716558; Milone et al. 2011. PubMed ID: 21670405; Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89866654-A-G). This variant is interpreted as likely pathogenic. -

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

Pathogenic:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.96

MVP

0.95

MPC

0.89

ClinPred

0.75

GERP RS

4.4

Varity_R

0.92

gMVP

0.94

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