rs150233690

Positions:

chr15-89319073-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_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. 14/21 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:17B:1

Conservation

PhyloP100: 1.50

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 Likely_benign. Variant got -6 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.3131T>C	p.Val1044Ala	missense_variant	20/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2403T>C		3_prime_UTR_variant	20/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.3131T>C	p.Val1044Ala	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.3131T>C	p.Val1044Ala	missense_variant	20/23	1	NM_002693.3	ENSP00000268124	P1

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

GnomAD3 exomes

AF:

0.000648

AC:

163

AN:

251418

Hom.:

AF XY:

0.000662

AC XY:

AN XY:

135886

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 SAS exome

AF:

0.000686

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

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000970

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000591

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000901

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:17Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2024	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 in a patient with mtDNA depletion syndrome with liver fibrosis and portal hypertension, and two other POLG variants with unknown phase (PMID: 28776642); Reported 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 supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28337550, 34426522, Singh2021[Poster], 32391929, 28776642, 21357833, 21880868) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2023	- -

Progressive sclerosing poliodystrophy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, 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.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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 30, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2022

- -

POLG-Related Spectrum Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 15, 2018

The POLG c.3131T>C (p.Val1044Ala) has been reported in four studies and in a total of five patients including one in a compound heterozygous state, and four in a heterozygous state (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). Two of the individuals identified with the variant have multiple sclerosis, two have mitochondrial disease, and the fifth was noted to have POLG-deficiency (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). The p.Val1044Ala variant was found in one control out of 1200 control individuals and is reported at a frequency of 0.003319 in the Other population of the Exome Aggregation Consortium. Based on the evidence, the p.Val1044Ala is classified as a variant of unknown significance, but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2018

- -

POLG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

May 27, 2021

- -

Early-onset Parkinson disease 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 15, 2020

- -

EEG abnormality

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

Dec 22, 2016

- -

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

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

MutationTaster

Benign

0.99

N;N

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

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