15-89330258-C-G

Position:

chr15-89330258-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_002693.3(POLG):c.678G>C(p.Gln226His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,611,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:6

Conservation

PhyloP100: 1.16

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07381511).

BP6

Variant 15-89330258-C-G is Benign according to our data. Variant chr15-89330258-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206581.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9}. Variant chr15-89330258-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
POLG	NM_002693.3 linkuse as main transcript	c.678G>C	p.Gln226His	missense_variant	3/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1 linkuse as main transcript	c.733G>C	p.Ala245Pro	missense_variant	3/23		NP_001393486.1
POLG	NM_001126131.2 linkuse as main transcript	c.678G>C	p.Gln226His	missense_variant	3/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.678G>C	p.Gln226His	missense_variant	3/23	1	NM_002693.3	ENSP00000268124	P1
POLGARF	ENST00000706918.1 linkuse as main transcript	c.733G>C	p.Ala245Pro	missense_variant	2/2			ENSP00000516626	P1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000896

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000408

AC:

101

AN:

247722

Hom.:

AF XY:

0.000409

AC XY:

AN XY:

134464

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000340

Gnomad NFE exome

AF:

0.000770

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000526

AC:

768

AN:

1459374

Hom.:

Cov.:

AF XY:

0.000519

AC XY:

377

AN XY:

726014

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000367

Gnomad4 NFE exome

AF:

0.000639

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.000519

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000896

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000578

Hom.:

Bravo

AF:

0.000457

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18156159, 21880868, 33600046) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 28, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	POLG: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2018	- -

Progressive sclerosing poliodystrophy

Benign:2

Likely benign, 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.678G>C (NP_002684.1:p.Gln226His) [GRCH38: NC_000015.10:g.89330258C>G] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 05, 2023

Variant summary: POLG c.678G>C (p.Gln226His) results in a non-conservative amino acid change located in the exonuclease domain (IPR041336) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 247722 control chromosomes (gnomAD). c.678G>C has been reported in the literature in individuals affected with POLG-Related Spectrum Disorders, including parkinsonism (Montaut_2018) and adult-onset chronic progressive external ophthalmoplegia (Heighton_2019) without strong evidence for causality, and as a compound heterozygous genotype together with a pathogenic variant in an individual diagnosed with sensory ataxic neuropathy with mtDNA deletions (Keller_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31521625, 33600046, 29913018). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant with conflicting assessments: VUS (n=9), likely benign (n=2), likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

POLG-Related Spectrum Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Jun 05, 2019

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2021

The c.678G>C (p.Q226H) alteration is located in exon 3 (coding exon 2) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 678, causing the glutamine (Q) at amino acid position 226 to be replaced by a histidine (H). The p.Q226H alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Institute of Human Genetics, Cologne University

Jan 30, 2024

- -

POLG-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2024

The POLG c.678G>C variant is predicted to result in the amino acid substitution p.Gln226His. This variant has been reported in the compound heterozygous state in an individual with infantile muscular atrophy and weakness (Keller et al. 2021. PubMed ID: 33600046). Additionally, this variant was reported in the heterozygous state in one patient with clinical features suggestive of POLG deficiency, although a second plausible causative variant was not identified (Tang et al. 2011. PubMed ID: 21880868, Supplementary Table 3). This variant is reported in 0.076% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autism;C0036572:Seizure

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

Aug 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Benign

-0.23

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.051

MetaRNN

Benign

0.074

MutationTaster

Benign

1.0

N;N

ClinPred

0.032

GERP RS

4.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

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