NM_002693.3:c.3151G>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_002693.3(POLG):c.3151G>C(p.Gly1051Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,614,150 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:3

Conservation

PhyloP100: 4.59

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 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 15-89319053-C-G is Pathogenic according to our data. Variant chr15-89319053-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13501.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.3151G>C	p.Gly1051Arg	missense_variant	Exon 20 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.3151G>C	p.Gly1051Arg	missense_variant	Exon 20 of 23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.3151G>C	p.Gly1051Arg	missense_variant	Exon 20 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251328

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Feb 04, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Sep 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with another pathogenic variant in POLG (phase unknown) in two siblings with developmental delay, epilepsy, ataxia, severe neuropathy, and/or achalasia (PMID: 28130605); Observed in an individual with sensory ataxia (PMID: 29482223); Published functional studies demonstrate a damaging effect, indicating that the G1051R variant results in increased mitochondrial DNA (mtDNA) instability and causes mtDNA defects (PMID: 17980715); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19010300, 14745080, 15913923, 20185557, 34426522, 32347949, 37470284, 36343308, 37202477, 27538665, 28130605, 17980715, 29482223, 37510298) -

Oct 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3_moderate + PM2_supporting + PS4_moderate +PM3 -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The POLG p.Gly1051Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs121918049) and in ClinVar (classified as conflicting interpretations of pathogenicity with one likely pathogenic submission by GeneDx, one VUS submission by Invitae and one pathogenic submission by OMIM; associated conditions are Progressive sclerosing poliodystrophy and Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis). The variant was not identified in Cosmic or LOVD3.0. The variant was found in control databases in 5 of 251328 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017) and observed in the following populations: European (non-Finnish) in 4 of 113636 chromosomes (freq: 0.000035) and Latino in 1 of 34582 chromosomes (freq: 0.000029), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. In a family study, sequencing of the POLG gene revealed two compound heterozygous mutations (G1051R and Y932H) in a 48-year-old male proband and his sister, both with a neurologic syndrome. Other family members, generally asymptomatic, carried each mutation in isolation and neither mutation was found in 120 control alleles (Mancuso_2004_PMID: 14745080). Functional studies have been conflicting with regards to the effect on mitochondrial DNA (mtDNA) instability and protein function (Baruffini_2017_PMID: 17980715; Stumpf_2010_PMID: 20185557; Chan_2009_PMID: 19010300). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly1051 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

POLG-Related Spectrum Disorders

Pathogenic:2

Feb 28, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLG c.3151G>C (p.Gly1051Arg) 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 2e-05 in 251328 control chromosomes. c.3151G>C has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders (e.g. Manusco_2004, Pozzo_2017, Coutelier_2018). This includes several patients with features of progressive external ophthalmoplegia who were compound heterozygous with pathogenic variants. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the equivalent mutation in yeast. This showed that the variant resulted in a substantial increase in mtDNA instability (Baruffini_2007). The following publications have been ascertained in the context of this evaluation (PMID: 14745080, 28130605, 17980715, 29482223). ClinVar contains an entry for this variant (Variation ID: 13501). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 23, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.3151G>C (p.Gly1051Arg) missense variant has been reported in a compound heterozygous state in at least three patients, including one pair of siblings (Mancuso et al. 2004; Formichi et al. 2016). One patient had developmental delay, epilepsy, ataxia, severe neuropathy, and achalasia, and the sibling pair had progressive external ophthalmoplegia. In one family, asymptomatic or oligosymptomatic relatives were reported to be heterozygous for the p.Gly1051Arg variant, and relatives who were oligosymptomatic did not have ptosis or ophthalmoplegia (Mancuso et al. 2004). This variant was absent from at least 120 control chromosomes but is reported at a frequency of 0.000036 in the European (non-Finnish) population from the Genome Aggregation Database. In a yeast model, the p.Gly1051Arg variant showed increased petite mutant frequency, signifying an increase in mtDNA instability, compared to wildtype when in a haploid state and slightly increased petite frequency when in a heterozygous state with wildtype (Baruffini et al. 2007). Further, when the p.Gly1051Arg variant was expressed in this yeast model in a compound heterozygous state with another missense variant, there was increased petite frequency compared to wildtype. Western blot analysis identified this variant expression was <10% of wildtype. Based on the evidence, the p.Gly1051Arg variant is considered likely pathogenic for POLG-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Progressive sclerosing poliodystrophy

Pathogenic:2

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1051 of the POLG protein (p.Gly1051Arg). This variant is present in population databases (rs121918049, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 14745080, 28130605, 30818899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13501). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715, 20185557). For these reasons, this variant has been classified as Pathogenic. -

Mar 15, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Pathogenic:1

Jan 27, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

See cases

Pathogenic:1

May 21, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS1, PM2, PM3, PP2 -

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

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant non-syndromic intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Heterozygous. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.3

D;D

REVEL

Pathogenic

0.91

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.050

T;T

Polyphen

0.99

D;D

Vest4

0.82

MutPred

0.94

Gain of MoRF binding (P = 0.0152);Gain of MoRF binding (P = 0.0152);

MVP

0.98

MPC

0.70

ClinPred

0.91

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.79

gMVP

0.79

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