rs181860632

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_002693.3(POLG):c.3139C>T(p.Arg1047Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,088 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:4O:1

Conservation

PhyloP100: 5.05

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:

POLGARF (HGNC:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 15-89319065-G-A is Pathogenic according to our data. Variant chr15-89319065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206548.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=10, not_provided=1, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3139C>T	p.Arg1047Trp	missense_variant	20/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2411C>T		3_prime_UTR_variant	20/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3139C>T	p.Arg1047Trp	missense_variant	20/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3139C>T	p.Arg1047Trp	missense_variant	20/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251358

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2020	PS4_moderate, PM2, PM3, PM5, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2024	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: 20818383, 31571979, 19251978, 22189570, 18195149, 29655203, 32347949, 35186329, 34690748, 37229156, 32613234, 38385069) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with autosomal recessive POLG-related disorders. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2017	- -

Progressive sclerosing poliodystrophy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1047 of the POLG protein (p.Arg1047Trp). This variant is present in population databases (rs181860632, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 18195149, 22189570). ClinVar contains an entry for this variant (Variation ID: 206548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLG related disorder (PMID:18195149, PS1_P). A different missense change at the same codon has been reported to be associated with POLG related disorder (PMID:12707443, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.848, 3CNET: 0.788, PP3_P). A missense variant is a common mechanism associated with Progressive external ophthalmoplegia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). . The variant has been reported to be in trans with a pathogenic variant as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

POLG-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The POLG c.3139C>T variant is predicted to result in the amino acid substitution p.Arg1047Trp. This variant was previously reported in the compound heterozygous or homozygous state in patients who presented with autosomal recessive Alpers’ syndrome, sensory neuropathy, or developmental delay and ataxia (Wiltshire et al. 2008. PubMed ID: 18195149; Lax et al. 2012. PubMed ID: 22189570; Supplementary data, Gorukmez et al. 2023. PubMed ID: 36964972). The c.3139C>T variant was also reported in two siblings who presented with progressive external ophthalmoplegia and/or ataxia; both patients harbored a second causative variant, although segregation analysis was not preformed (Stewart et al. 2009. PubMed ID: 19251978). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. A different amino acid substitution at this position (p.Arg1047Gln) was also reported to be causative for disease (Agostino et al. 2003. PubMed ID: 12707443). This variant is interpreted as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 12, 2024

Variant summary: POLG c.3139C>T (p.Arg1047Trp) 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 4e-05 in 251358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.3139C>T has been reported in the literature in compound heterozygous individuals affected with Alpers disease (e.g. Wiltshire_2008) or progressive external ophthalmoplegia (e.g. Stewart_2009), or as a heterozygous genotype in an individual affected with mitochondrial complex I disorder without strong evidence for causality (e.g. Calvo_2010). These data indicate that the variant may be associated with disease. 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: 20818383, 29655203, 19251978, 18195149). ClinVar contains an entry for this variant (Variation ID: 206548). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.3139C>T (p.R1047W) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the arginine (R) at amino acid position 1047 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C1843852:Spinocerebellar ataxia with epilepsy

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 11-30-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.88

MVP

0.99

MPC

0.67

ClinPred

0.80

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.46

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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