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rs113994097

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The NM_002693.3(POLG):c.2243G>C(p.Trp748Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,612,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W748C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

10
4
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36O:2

Conservation

PhyloP100: 7.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002693.3
PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
PP5
Variant 15-89323426-C-G is Pathogenic according to our data. Variant chr15-89323426-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89323426-C-G is described in Lovd as [Pathogenic]. Variant chr15-89323426-C-G is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.082895756).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLGNM_002693.3 linkuse as main transcriptc.2243G>C p.Trp748Ser missense_variant 13/23 ENST00000268124.11
POLGARFNM_001406557.1 linkuse as main transcriptc.*1515G>C 3_prime_UTR_variant 13/23
POLGNM_001126131.2 linkuse as main transcriptc.2243G>C p.Trp748Ser missense_variant 13/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.2243G>C p.Trp748Ser missense_variant 13/231 NM_002693.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000742
AC:
113
AN:
152210
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00641
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000514
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000971
AC:
244
AN:
251290
Hom.:
0
AF XY:
0.000987
AC XY:
134
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00601
Gnomad NFE exome
AF:
0.000950
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000730
AC:
1066
AN:
1460716
Hom.:
1
Cov.:
31
AF XY:
0.000736
AC XY:
535
AN XY:
726750
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00631
Gnomad4 NFE exome
AF:
0.000617
Gnomad4 OTH exome
AF:
0.000547
GnomAD4 genome
AF:
0.000742
AC:
113
AN:
152210
Hom.:
0
Cov.:
33
AF XY:
0.00108
AC XY:
80
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00641
Gnomad4 NFE
AF:
0.000514
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000506
Hom.:
0
Bravo
AF:
0.000310
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000832
AC:
101
EpiCase
AF:
0.000763
EpiControl
AF:
0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:36Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:13Other:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 02, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 21, 2020In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalFeb 15, 2017- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsMar 15, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 09, 2023- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 30, 2021- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncJun 24, 2020The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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. -
Progressive sclerosing poliodystrophy Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 31, 2022This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 01, 2018The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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. -
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeJan 25, 2024This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), 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 disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). 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. -
Pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized MedicineMay 26, 2023- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 28, 2022- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 20, 2023- -
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:4
Pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsOct 31, 2023This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268). -
Pathogenic, flagged submissionclinical testingMayo Clinic Laboratories, Mayo ClinicMar 19, 2018- -
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
POLG-Related Spectrum Disorders Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 23, 2018The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 12, 2023Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Mitochondrial DNA depletion syndrome 4b Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenJul 28, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJun 10, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4. -
Mitochondrial disease Pathogenic:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedclinical testingWellcome Centre for Mitochondrial Research, Newcastle UniversityApr 07, 2017- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 25, 2017- -
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 04, 2018The p.W748S pathogenic mutation (also known as c.2243G>C), located in coding exon 12 of the POLG gene, results from a G to C substitution at nucleotide position 2243. The tryptophan at codon 748 is replaced by serine, an amino acid with highly dissimilar properties. This variant is a well described founder mutation, accounting for up to 8% of disease causing alleles in the Finnish population. Additionally, this mutation has been described many times in the homozygous and compound heterozygous states in individuals with Alpers-Huttenlocher syndrome (AHS), SANDO, MEMSA, and other autosomal recessive POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, myopathy, tremors, cognitive decline, and hearing loss (Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83; Janssen W et al. Acta Neurol Belg, 2016 Mar;116:17-25; Uusimaa J et al. Epilepsia, 2008 Jun;49:1038-45; Henao AI et al. Neuroradiol J, 2016 Feb;29:46-8; Masingue M et al. Mitochondrion, 2018 Feb; Hikmat O et al. Int J Mol Sci, 2017 Aug;18:). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
POLG-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 01, 2024The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. -
Spinocerebellar ataxia with epilepsy Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.49
Cadd
Pathogenic
31
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.80
D;D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.083
T;T
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Benign
2.0
M;M
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.3
D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.024
D;D
Sift4G
Benign
0.13
T;T
Polyphen
1.0
D;D
Vest4
0.90
MVP
0.97
MPC
0.85
ClinPred
0.13
T
GERP RS
5.6
Varity_R
0.90
gMVP
0.85

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.

Other links and lift over

dbSNP: rs113994097; hg19: chr15-89866657; API