rs147282197

Positions:

• chr15-89330258-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 1.16

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_002693.3
• 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: {Uncertain_significance=10, Likely_benign=2}. Variant chr15-89330258-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.678G>C	p.Gln226His	missense_variant	3/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.733G>C	p.Ala245Pro	missense_variant	3/23
POLG	NM_001126131.2	c.678G>C	p.Gln226His	missense_variant	3/23

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152256 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000409 AC XY: 55 AN XY: 134464

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.: 0 Cov.: 32 AF XY: 0.000519 AC XY: 377 AN XY: 726014

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: 79 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74380

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.: 0

Bravo AF: 0.000457

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2023	In silico analysis supports 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	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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	POLG: PM2, BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	Invitae	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. -

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

- -

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. -

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

- -

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	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	-0.23
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.074	T
MutationTaster	Benign	1.0	N;N
ClinPred		0.032	T
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

Other links and lift over

dbSNP: rs147282197; hg19: chr15-89873489;