NM_002693.3:c.32G>A

Variant names:

• chr15-89333723-C-T
• rs765472726
• NM_002693.3:c.32G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002693.3(POLG):​c.32G>A​(p.Gly11Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,536,106 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G11A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:1
• Conservation: PhyloP100: 0.239
• Publications: 10 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011898369).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	NP_002684.1
	POLGARF	NM_001430120.1	MANE Select	c.87G>A	p.Arg29Arg	synonymous	Exon 1 of 2	NP_001417049.1
	POLG	NM_001126131.2		c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.32G>A	p.Gly11Asp	missense	Exon 2 of 23	ENSP00000399851.2
	POLGARF	ENST00000706918.1	MANE Select	c.87G>A	p.Arg29Arg	synonymous	Exon 1 of 2	ENSP00000516626.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.000456

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000168 AC: 22 AN: 130892 AF XY: 0.000168

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 708 AN: 1383918 Hom.: 1 Cov.: 32 AF XY: 0.000477 AC XY: 326 AN XY: 683090

African (AFR) AF: 0.000127 AC: 4 AN: 31616

American (AMR) AF: 0.0000560 AC: 2 AN: 35738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35756

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.000625 AC: 674 AN: 1078880

Other (OTH) AF: 0.000467 AC: 27 AN: 57858

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74346

African (AFR) AF: 0.000121 AC: 5 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68026

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000169 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 14, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 29, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). In multiple reported cases, this variant has been observed on the same chromosome (in cis) as c.2554C>T (p.R852C) (PMID:18487244, 19251978, 21880868, 22494076). In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools disagree on the variant's effect on normal protein function.

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG: PM2, PM3:Supporting

Sep 11, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G11D variant has also been observed in individuals with POLG-related disorders but typically reported to occur on the same chromosome (in cis) with R852C with a pathogenic variant on the other allele (for examples, see Ashley et al., 2009; Tang et al., 2011, Human DNA Polymerase Gamma Mutation Database). In one such observation, authors concluded that G11D was likely a non-pathogenic polymorphism that may serve as a modifier variant (Stewart et al., 2009). The G11D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, it alters a position that is not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

POLG-related disorder Uncertain:2

Apr 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3

May 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The POLG c.32G>A variant is predicted to result in the amino acid substitution p.Gly11Asp. This variant has been reported in multiple individuals with POLG-related disorders; however, it is almost exclusively seen on the same allele (in cis) with the known pathogenic variant p.Arg852Cys (Calvo et al. 2010. PubMed ID: 20818383; Ashley et al. 2008. PubMed ID: 18487244; Stewart et al. 2009. PubMed ID: 19251978; Wong et al. 2008. PubMed ID: 18546365). In many patients with the [G11D;R852C] allele, an additional POLG variant is reported on the opposite allele indicating recessive inheritance (Squires et al. 2023. PubMed ID: 37184518:Martin-Saavedra et al. 2021. PubMed ID: 34052969). It has been suggested in some reports that the p.Gly11Asp variant may have a synergistic effect when also present with the p.Arg852Cys variant; however, conclusive evidence for this proposal is not available (Ashley et al. 2008. PubMed ID: 18487244; Stewart et al. 2009. PubMed ID: 19251978; Wong et al. 2008. PubMed ID: 18546365) The c.32G>A variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/195182/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Progressive sclerosing poliodystrophy Uncertain:1 Benign:1

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 11 of the POLG protein (p.Gly11Asp). This variant is present in population databases (rs765472726, gnomAD 0.04%). This missense change has been observed in individual(s) with POLG-related disorders, however these individuals also carried an additional pathogenic POLG variant on the same allele (in cis) (PMID: 18487244, 19251978, 21880868, 22494076). ClinVar contains an entry for this variant (Variation ID: 195182). 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 not expected to disrupt POLG protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.32G>A (NP_002684.1:p.Gly11Asp) [GRCH38: NC_000015.10:g.89333723C>T] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18487244 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.

not specified Uncertain:1

Mar 26, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLG c.32G>A (p.Gly11Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 130892 control chromosomes. c.32G>A has been reported in the literature in individuals affected with features of POLG-Related Spectrum Disorders (e.g. Ashley_2008, Wong_2008, Stewart_2009, Naess_2009, Calvo_2010, Mehta_2011, Tang_2011, Vasta_1012, Alves_2020, Hikmat_2020, Martin-Saavedra_2022). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. Co-occurrences with other pathogenic variants in cis were reported in many patients (POLG c.2554C>T, p.Arg852Cys; POLG c.1880G>A, p.Arg627Gln), providing supporting evidence for a benign role. 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: 18487244, 18546365, 19251978, 19103152, 20818383, 21880868, 22494076, 21259344, 32391929, 32445240, 34052969). ClinVar contains an entry for this variant (Variation ID: 195182). Based on the evidence outlined above, the variant was classified as uncertain significance.

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 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLG-Related Spectrum Disorders Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Inborn genetic diseases Uncertain:1

May 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32G>A (p.G11D) alteration is located in exon 2 (coding exon 1) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 32, causing the glycine (G) at amino acid position 11 to be replaced by an aspartic acid (D). Based on the available evidence, the clinical significance of the POLG c.32G>A (p.G11D) alteration is uncertain for autosomal recessive POLG-related mitochondrial disorders; however, the association of this alteration with autosomal dominant progressive external ophthalmoplegia is unlikely. Based on data from gnomAD, the A allele has an overall frequency of 0.02% (27/162250) total alleles studied. The highest observed frequency was 0.04% (23/64876) of European (non-Finnish) alleles. This variant was confirmed in cis with p.R852C in three individuals with a third POLG variant in trans; two individuals presented with epilepsy and hepatopathy and the third had a clinical diagnosis of polymerase gamma-1 deficiency (Ashley, 2008; Blankenberg, 2012). It was also identified in cis with p.R627Q and in trans with p.R852C in an individual with seizures, liver dysfunction, and progressive external ophthalmoplegia (Wong, 2008). The p.G11D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Hereditary spastic paraplegia Uncertain:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.24
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.39
MVP		0.61
MPC		0.20
ClinPred		0.040	T
GERP RS		0.34
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.49
Mutation Taster		=35/65	disease causing

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

Other links and lift over

dbSNP: rs765472726; hg19: chr15-89876954; COSMIC: COSV51524197; COSMIC: COSV51524197;