rs551811489

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_002693.3(POLG):c.2977C>T(p.Arg993Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,613,030 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 6.43

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.2977C>T	p.Arg993Cys	missense_variant	Exon 18 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.2977C>T	p.Arg993Cys	missense_variant	Exon 18 of 23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.2977C>T	p.Arg993Cys	missense_variant	Exon 18 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250286

Hom.:

AF XY:

0.0000960

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000694

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:

0.00000885

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460714

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000693

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

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:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2024	Reported in an individual with onset of Parkinson disease at age 72 who also harbored two additional POLG variants, one of which was considered pathogenic (PMID: 24122062); 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: 30941926, 32502631, 24122062) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 12, 2023

Variant summary: POLG c.2977C>T (p.Arg993Cys) 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. 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 0.00011 in 250286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.2977C>T has been reported in the literature in at-least one individual affected with features of Parkinsons Disease (example, Ylonen_2013 cited in Hsieh_2019). These data do not allow any conclusion about variant significance. 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: 30941926, 24122062). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 14, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2019

The p.R993C variant (also known as c.2977C>T), located in coding exon 17 of the POLG gene, results from a C to T substitution at nucleotide position 2977. The arginine at codon 993 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in conjunction with two additional POLG vairants in an individual with parkinsonism without progressive external ophthalmoplegia (Hsieh PC et al. Brain Behav, 2019 May;9:e01281). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

POLG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The POLG c.2977C>T variant is predicted to result in the amino acid substitution p.Arg993Cys. This variant was reported in an individual with late-onset Parkinson disease (Ylönen et al 2013. PubMed ID: 24122062). This variant is reported in 0.069% of alleles in individuals of Latino 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 sclerosing poliodystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2025

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 993 of the POLG protein (p.Arg993Cys). This variant is present in population databases (rs551811489, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 405570). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.69

Gain of catalytic residue at W994 (P = 8e-04);Gain of catalytic residue at W994 (P = 8e-04);

MVP

0.95

MPC

0.32

ClinPred

0.87

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.77

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