rs201732356

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.3286 C>T (p.Arg1096Cys) variant in POLG is seen at an allele frequency of 0.00001 in gnomAd and 0.00002 in ExAC with no homozygotes (PM2). This variant has a Revel score of 0.837 (PP3). There are 7 cases in the literature reported with an Alpers phenotype in individuals who are homozygous for the c.3286 C>T (p.Arg1096Cys) (PM3_strong; PMID:21305355; PMID:21880868; PMID:18546365). There are also 6 cases reported with other pathogenic variants with phasing unknown 2 siblings reported compound heterozygous with Thr914Pro, another reported with Trp748Ser, another cases with Leu591Phe, another case with Ala467Thr, and another case with Gly848Ser. Each case was reported with POLG related disease with Alpers, liver related disease, and other neurological phenotypes (PM3_strong; PMID:18487244; PMID:30021052; PMID:24265579; PMID:27111573; PMID:21880868). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PM2, PP3, PM3_strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA316756/MONDO:0044970/014

Frequency

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

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:16

Conservation

PhyloP100: 4.23

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 7 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.3286C>T	p.Arg1096Cys	missense_variant	21/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 linkuse as main transcript	c.3286C>T	p.Arg1096Cys	missense_variant	21/23		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2558C>T		3_prime_UTR_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3286C>T	p.Arg1096Cys	missense_variant	21/23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251284

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000168

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -
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.3286C>T (NP_002684.1:p.Arg1096Cys) [GRCH38: NC_000015.10:g.89318737G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12707443 ; 21305355 . 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1096 of the POLG protein (p.Arg1096Cys). This variant is present in population databases (rs201732356, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive POLG-related disease (PMID: 21305355, 21880868, 22189570, 24265579, 28471437, 30167885). This variant has been reported in individual(s) with autosomal dominant progressive external ophthalmoplegia (PMID: 12707443); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 206556). 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 have shown that this missense change affects POLG function (PMID: 20185557, 23208208). This variant disrupts the p.Arg1096 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 16621917, 19752458), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206556). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 18487244 , 18546365 , 21305355 , 21880868 , 24265579 , 27111573 , 30021052). Different missense changes at the same codon (p.Arg1096Gly, p.Arg1096His, p.Arg1096Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000206555 , VCV000206557 , VCV000206559). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2022	Reported previously in multiple patients with Alpers syndrome, a clinical presentation suggestive of POLG deficiency, or progressive external ophthalmoplegia (arPEO) and peripheral neuropathy, who were either homozygous for the R1096C variant (Mohamed et al., 2011; Wong et al, 2008; Tang et al., 2011; Ashley et al. 2008) or compound heterozygous for the R1096C variant and another pathogenic variant (Tang et al., 2011; Ashley et al., 2008; Lax et al., 2012); Functional studies have demonstrated that the R1096C variant results in a decreased catalytic efficiency in incorporating correct dNTP into DNA (Sohl et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28471437, 29655203, 22189570, 24265579, 21305355, 12707443, 25129007, 23545419, 19578034, 25786813, 20164463, 21880868, 18487244, 23208208, 21138766, 29474836, 30167885, 31521625, 31130284) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Mitochondrial disease

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

May 23, 2021

The c.3286 C>T (p.Arg1096Cys) variant in POLG is seen at an allele frequency of 0.00001 in gnomAd and 0.00002 in ExAC with no homozygotes (PM2). This variant has a Revel score of 0.837 (PP3). There are 7 cases in the literature reported with an Alpers phenotype in individuals who are homozygous for the c.3286 C>T (p.Arg1096Cys) (PM3_strong; PMID:21305355; PMID:21880868; PMID:18546365). There are also 6 cases reported with other pathogenic variants with phasing unknown 2 siblings reported compound heterozygous with Thr914Pro, another reported with Trp748Ser, another cases with Leu591Phe, another case with Ala467Thr, and another case with Gly848Ser. Each case was reported with POLG related disease with Alpers, liver related disease, and other neurological phenotypes (PM3_strong; PMID:18487244; PMID:30021052; PMID:24265579; PMID:27111573; PMID:21880868). In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PM2, PP3, PM3_strong -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 31, 2024

Variant summary: POLG c.3286C>T (p.Arg1096Cys) 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. 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 8e-06 in 251284 control chromosomes. c.3286C>T has been reported in the literature in multiple individuals affected with autosomal recessive POLG-related disorders and in at least one patient with autosomal dominant progressive external ophthalmoplegia (e.g. Tang_2011, Agostino_2003). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.3287G>A, p.Arg1096His), supporting the critical relevance of codon 1096 to POLG protein function. At least one publication reports that this variant causes reduced incorporation efficiency of a correct deoxyribonucleotide triphosphate (dNTP) in vitro (e.gSohl_2013). The following publications have been ascertained in the context of this evaluation (PMID: 12707443, 23208208, 21880868). ClinVar contains an entry for this variant (Variation ID: 206556). While this variant has been observed in individuals affected with autosomal dominant progressive external ophthalmoplegia, the clinical significance of the variant in this condition is currently unclear. Based on the evidence outlined above, this variant is pathogenic for autosomal recessive POLG-related disorders. -

POLG-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The POLG c.3286C>T variant is predicted to result in the amino acid substitution p.Arg1096Cys. This variant has been reported to be causative for autosomal recessive POLG-associated disorders such as sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), progressive external ophthalmoplegia (PEO) and sensory neuropathy, and Alpers’ Syndrome (Kurt et al. 2012. PMID: 24265579; Lax et al. 2012. PMID: 22189570; Ashley et al. 2008. PMID: 18487244; Hikmat et al. 2017. PubMed ID: 28471437). At least one heterozygous carrier of this particular variant presented with sporadic PEO (Agostino et al. 2003. PMID: 12707443). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89861968-G-A). This variant is interpreted as pathogenic. -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Mitochondrial DNA depletion syndrome 4b

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Childhood myocerebrohepatopathy spectrum

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University

The p.Arg1096Cys variant in POLG gene has been previously reported many times with autosomal recessive inheritance pattern. Homozygous mutation of this variant was reported in a Saudi child with Alpers-Huttenlocher syndrome (AHS) (Kentab, 2019). Other reports could be accessed in The POLG Pathogenicity Prediction Server (http://polg.bmb.msu.edu). -

Recessive mitochondrial ataxia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS1,PS3,PP1,PM2, PP3, PM3_strong -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.5

M;M

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.94

P;P

Vest4

0.94

MVP

0.97

MPC

0.77

ClinPred

0.99

GERP RS

4.4

Varity_R

0.90

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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