rs121918054

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_002693.3(POLG):c.2209G>C(p.Gly737Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00162 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 1 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30U:1

Conservation

PhyloP100: 6.01

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_pathogenic. Variant got 8 ACMG points.

PP5

Variant 15-89323460-C-G is Pathogenic according to our data. Variant chr15-89323460-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89323460-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.2209G>C	p.Gly737Arg	missense_variant	13/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.*1481G>C		3_prime_UTR_variant	13/23
POLG	NM_001126131.2 linkuse as main transcript	c.2209G>C	p.Gly737Arg	missense_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.2209G>C	p.Gly737Arg	missense_variant	13/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

139

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000688

AC:

173

AN:

251378

Hom.:

AF XY:

0.000699

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00169

AC:

2474

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1163

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00206

Gnomad4 OTH exome

AF:

0.00257

GnomAD4 genome

AF:

0.000913

AC:

139

AN:

152318

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00160

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.000937

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00180

EpiControl

AF:

0.00130

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:30Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	POLG: PM3:Very Strong, PM2:Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 11, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 18546365, 21880868). This variant has been identified in multiple unrelated individuals with autosomal recessive POLG-related disorders and appears to segregate with disease in at least one family. Affected heterozygous individuals have also been reported. 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. Computational tools predict that this variant is damaging. -
Uncertain significance, no assertion criteria provided	provider interpretation	Inherited Neuropathy Consortium	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2019	The POLG c.2209G>C; p.Gly737Arg variant (rs121918054) is reported in the literature in multiple individuals with symptoms or diagnoses of a POLG-associated disorder, including mitochondrial DNA depletion syndrome, progressive external ophthalmoplegia, early-onset parkinsonism, and sensorimotor neuropathy (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Multiple affected individuals also carried a second pathogenic variant, with parental testing confirming compound heterozygosity of several probands (Davidzon 2006, Harrower 2008, Horvath 2006, Milone 2008, Tzoulis 2009, Wong 2008). Additionally, the p.Gly737Arg variant was reported to co-segregate with autosomal recessive disease in at least two families (Davidzon 2006, Harrower 2008). This variant is found in the non-Finnish European population with an overall allele frequency of 0.13% (171/129104 alleles) in the Genome Aggregation Database. The glycine at codon 737 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Bereau M et al. The wide POLG-related spectrum: An integrated view. J Neurol Sci. 2016 Sep 15;368:70-6. Davidzon G et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006 May;59(5):859-62. Harrower T et al. POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease. Arch Neurol. 2008 Jan;65(1):133-6. Horvath R et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Milone M et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008 Aug;18(8):626-32. Stumpf JD et al. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol. 2013 Apr 1;5(4):a011395. Tzoulis C et al. Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations. Acta Neurol Scand Suppl. 2009;(189):38-41. Wong LJ et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008 Sep;29(9):E150-72. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 25, 2023	PP1, PP3, PM3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16634032, 24725338, 18546365, 25356970, 30609409, 31521625, 16621917, 21880868, 19566497, 27185166, 27016405, 27349602, 28812649, 29655203, 30843307, 31731261, 31980526, 34062649, 33300680, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Progressive sclerosing poliodystrophy

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
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.2209G>C (NP_002684.1:p.Gly737Arg) [GRCH38: NC_000015.10:g.89323460C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 737 of the POLG protein (p.Gly737Arg). This variant is present in population databases (rs121918054, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16634032, 18546365, 18585914, 19566497, 24725338). 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: 13513). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 29, 2019	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 21, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Dec 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 08, 2021	The POLG c.2209G>C variant is classified as Likely Pathogenic (PS4_Moderate, PM3_Strong, PP3, PP5) -

POLG-Related Spectrum Disorders

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 23, 2016	The p.Gly737Arg (NM_002693.2 c.2209G>C) variant in POLG has been reported in 10 compound heterozygous individuals presenting with POLG-related mitochondrial DNA (mtDNA) depletion syndromes (Horvath 2006, Davidzon 2006, Wong 2008, Harrower 2 008, Tzoulis 2009, Tang 2011). This variant has been identified in 0.1% (67/6651 4) of European chromosomes in ExAC though this frequency in consistent with a re cessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p. Gly737Arg variant is likely pathogenic for POLG-related mitochondrial DNA (mtDNA) depletion syndromes in an autosomal recessive manner based upon biallelic case observations and consisten t allele frequency. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 31, 2022	Variant summary: POLG c.2209G>C (p.Gly737Arg) results in a non-conservative amino acid change located in the linker region (Wong_2008) 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 0.00069 in 251378 control chromosomes. c.2209G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders (example, Davidzon_2006, Milone_2008, Wong_2008, Tzoulis_2009, Stewart_2011, Sitarz_2014, Phillips_2019, Bychkov_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 16, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The c.2209G>C (p.G737R) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2209, causing the glycine (G) at amino acid position 737 to be replaced by an arginine (R). for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant POLG-related progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.07% (211/282774) total alleles studied. The highest observed frequency was 0.13% (171/129104) of European (non-Finnish) alleles. This is a well described common POLG mutation, having been detected with a frequency of close to 4% of alleles in affected individuals. In several studies, it has been detected in the compound heterozygous state in individuals exhibiting a wide range of phenotypes: from adult onset muscle weakness, myopathy, neuropathy, and ataxia, to early onset liver failure, seizures, and childhood death (Davidzon, 2006; Horvath, 2006; Harrower, 2008; Milone, 2008; Tzoulis, 2009; Tang, 2011; Rempe, 2016; Farwell, 2015; Phillips, 2019). 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 pathogenic. -

Mitochondrial disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Apr 07, 2017

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Dec 22, 2021

PM3_Strong, PP1, PP3 -

Hereditary spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

POLG-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The POLG c.2209G>C variant is predicted to result in the amino acid substitution p.Gly737Arg. This variant has been reported along with a second POLG variant in several individuals with mitochondrial DNA maintenance disorders which include progressive external opthalmoplegia, Charcot-Marie-Tooth Disease, and early-onset Parkinsonism (see for examples Tzoulis et al. 2009. PubMed ID: 19566497; Harrower et al. 2008. PubMed ID: 18195151; Davidzon et al. 2006. PubMed ID: 16634032; Rempe et al. 2016. PubMed ID: 27185166). This variant has also been reported in the absence of a second POLG variant in multiple individuals with mitochondrial disease (Wong et al. 2008. PubMed ID: 18546365). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a cause of autosomal dominant disease. This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13513). Given all the evidence, we too interpret c.2209G>C (p.Gly737Arg) as pathogenic for autosomal recessive POLG-related disorders. -

Tip-toe gait

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Jan 10, 2023

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

POLG NM_002693 exon 13 p.Gly737Arg (c.2209G>C): This variant has been reported in the literature in several individuals with various presentations of POLG-related disease (neuropathy, seizures, chronic progressive external opthalmoplegia (CPEO), ptosis, myopathy or early parkinsonism) as compound heterozygotes, segregating with disease in at least 1 affected family member (Davidzon 2006 PMID:16634032, Horvath 2006 PMID:16621917, Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365, Tzoulis 2009 PMID:19566497, Tang 2011 PMID:21880868, Sitarz 2014 PMID:247253378, Rempe 2016 PMID:27185166). This variant has also been reported as heterozygous in at least 3 individuals with POLG-related presentations, as well as in 1 individual with Charcot-Marie-Tooth disease Type 2, segregating with disease in 1 sibling (Harrower 2008 PMID:18195151, Wong 2008 PMID:18546365). This variant is present in 0.1% (162/126642) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121918054). This variant is present in ClinVar with several entries, though the interpretation among labs is inconsistent (Variation ID:13513). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but the high presence of this variant in the general population, variable clinical presentation in reported individuals and inconsistent community consensus interpretation of this variant suggests that further evidence for pathogenicity is required. Therefore, this variant classified as likely pathogenic. -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.86

Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);

MVP

0.98

MPC

0.72

ClinPred

0.12

GERP RS

5.6

Varity_R

0.64

gMVP

0.90

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