chr15-89329055-A-C

Position:

chr15-89329055-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_002693.3(POLG):c.911T>G(p.Leu304Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.32

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 Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 15-89329055-A-C is Pathogenic according to our data. Variant chr15-89329055-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89329055-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3 linkuse as main transcript	c.911T>G	p.Leu304Arg	missense_variant	4/23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 linkuse as main transcript	c.911T>G	p.Leu304Arg	missense_variant	4/23		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001406557.1 linkuse as main transcript	c.*183T>G		3_prime_UTR_variant	4/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.911T>G	p.Leu304Arg	missense_variant	4/23	1	NM_002693.3	ENSP00000268124.5		P54098

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

247470

Hom.:

AF XY:

0.0000822

AC XY:

AN XY:

133898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460830

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy

Pathogenic:5

Likely 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.911T>G (NP_002684.1:p.Leu304Arg) [GRCH38: NC_000015.10:g.89329055A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:11431686 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 17, 2022	The variant c.911 T>G (p.Leu304Arg) is present in compound heterozygous state with c.368 T>G (p.Val123Gly) in POLG gene. The four month old patient had two episodes of pneumonia and Acute Respiratory Distress Syndrome. Other clinical features observed were severe sepsis, shock, reduced IgG and increased levels of CK, Ferritin, SGOT and FGF-21. This variant has been present in 0.036% in gnomAD and 0.0074% in ExAc. The c.911 variant was observed 'in trans' with c.368 variant as both segregated separately in mother and father of the proband. This variant has been reported previously PMID: 32567010. Based on segregation studies and the clinical features, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the POLG protein (p.Leu304Arg). This variant is present in population databases (rs121918044, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 11431686, 16639411, 21880868, 22006280, 24288107). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13497). 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: 20601675, 26095671). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Oct 17, 2022	A Hetrozygous variation in exon 4 of the POLG gene that results in the aminoacid substitution of Arginine for Leucine at codon 304 was detected.The observed variant c.911T>G (p.Leu304Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species.In summary, the variant meets our criteria to be classified as pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24288107, 20601675, 16639411, 21880868, 16368709, 22006280, 11431686, 30634555, 31521625, 32161153, 31589614, 33469851) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 21, 2017	- -

POLG-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 15, 2024	The POLG c.911T>G variant is predicted to result in the amino acid substitution p.Leu304Arg. This variant has been reported in the compound heterozygous or homozygous states in patients with a POLG-related disorder, such as Alpers-Huttenlocher syndrome, autosomal recessive progressive external ophthalmoplegia, or sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) (Spiegler et al. 2011. PubMed ID: 22006280; Szczepanowska et al. 2010. PubMed ID: 20601675). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -

Abnormality of the mitochondrion

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.88

Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);

MVP

0.99

MPC

0.80

ClinPred

0.82

GERP RS

5.8

Varity_R

0.92

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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