rs769827124

Positions:

chr15-89322749-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_002693.3(POLG):c.2419C>T(p.Arg807Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R807P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 5.27

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 15-89322749-G-A is Pathogenic according to our data. Variant chr15-89322749-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 279982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.2419C>T	p.Arg807Cys	missense_variant	14/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.2419C>T	p.Arg807Cys	missense_variant	14/23		NP_001119603.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.2419C>T	p.Arg807Cys	missense_variant	14/23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250946

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135710

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:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:3

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.2419C>T (NP_002684.1:p.Arg807Cys) [GRCH38: NC_000015.10:g.89322749G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16919951 ; 21550804 . 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	Baylor Genetics	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 807 of the POLG protein (p.Arg807Cys). This variant is present in population databases (rs769827124, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive POLG-related disorders (PMID: 16919951, 21357833, 28471437). ClinVar contains an entry for this variant (Variation ID: 279982). 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). This variant disrupts the p.Arg807 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 14635118, 21880868, 28471437), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21880868, 21550804, 16919951, 21357833, 20185557, 28471437, 29655203, 30423451, 33671400, 34179544, 33511646, 30936349, 34052969, 33600046) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	POLG: PM1, PM2, PM3, PM5, PP3, PS3:Supporting -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, Cologne University

Sep 30, 2020

- -

POLG-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The POLG c.2419C>T variant is predicted to result in the amino acid substitution p.Arg807Cys. This variant has been reported in the heterozygous state in multiple individuals with epilepsy or proximal myopathy ptosis diplopia (Table S4, Lindy et al. 2018. PubMed ID: 29655203; Supplemental Table 4, Truty et al. 2019. PubMed ID: 31440721; Ferreira et al. 2011. PubMed ID: 21550804), along with a second POLG variant in multiple individuals with POLG deficiency disorders (see for example, Gago et al. 2006. PubMed ID: 16919951; Ferreira et al. 2011. PubMed ID: 21550804; Keller et al. 2021. PubMed ID: 33600046), and has appeared to segregate with POLG deficiency disorder in at least one family (Supplemental file 1, Hikmat et al. 2017. PubMed ID: 28471437). A functional in vivo study using budding yeast indicates that this variant decreases polymerase activity leading to reduced or depleted mtDNA resulting in mitochondrial disease (Stumpf et al. 2010. PubMed ID: 20185557). Alternate nucleotide changes affecting the same amino acid (p.Arg807Pro, p.Arg807His) have been reported in individuals affected with POLG deficiency disorders (Di Fonzo et al. 2003. PubMed ID: 14635118; Gago et al. 2006. PubMed ID: 16919951; Supplemental file 1, Hikmat et al. 2017. PubMed ID: 28471437). The c.2419C>T variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 10, 2024

- -

Neonatal seizure

Uncertain:1

Uncertain significance, flagged submission

clinical testing

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

Jun 15, 2017

present with homozygous ALDH7A1 pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.78

MutPred

0.94

Gain of catalytic residue at S809 (P = 0.0286);Gain of catalytic residue at S809 (P = 0.0286);

MVP

0.99

MPC

0.77

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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