rs562847013

Positions:

• chr15-89333364-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002693.3(POLG):​c.391T>C​(p.Tyr131His) variant causes a missense change. The variant allele was found at a frequency of 0.000308 in 1,575,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 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 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:1
• Conservation: PhyloP100: 3.59

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]

POLGARF (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03733334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.391T>C	p.Tyr131His	missense_variant	2/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.391T>C	p.Tyr131His	missense_variant	2/23		NP_001119603.1
POLGARF	NM_001406557.1	c.446T>C	p.Leu149Pro	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.391T>C	p.Tyr131His	missense_variant	2/23	1	NM_002693.3	ENSP00000268124.5
POLGARF	ENST00000706918.1	c.446T>C	p.Leu149Pro	missense_variant	1/2			ENSP00000516626.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000198 AC: 37 AN: 186608 Hom.: 0 AF XY: 0.000216 AC XY: 22 AN XY: 102040

Gnomad AFR exome AF: 0.0000924

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.000200

GnomAD4 exome AF: 0.000314 AC: 447 AN: 1423502 Hom.: 0 Cov.: 32 AF XY: 0.000317 AC XY: 224 AN XY: 705748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000751

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000111

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000221

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74492

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.000257

ExAC AF: 0.000218 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2024	Reported as an unclassified variant in an individual with a clinical presentation suggestive of POLG deficiency; additional clinical information was not provided and information regarding parental testing was not available (PMID: 21880868); Reported as a benign variant in an individual with multiple mtDNA deletions; no clinical information was provided (PMID: 16401742); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21880868, 16401742) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2017	The p.Tyr131His variant (rs562847013) has been reported as a polymorphism in an individual diagnosed with mitochondrial disease and as an unclassified variant in an individual whose features were suggestive of POLG deficiency; however, inheritance and specific clinical information were not reported for these cases (González-Vioque 2006 and Tang 2011). The p.Tyr131His variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.037% in the non-Finnish European population (identified in 34 out of 92,102 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 206492). The tyrosine at codon 131 is weakly conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Therefore, based on the available information, the clinical significance of the p.Tyr131His variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	POLG: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2023	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) Computational tools predict that this variant is not damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2019	- -

Progressive sclerosing poliodystrophy Uncertain:1 Benign:1

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.391T>C (NP_002684.1:p.Tyr131His) [GRCH38: NC_000015.10:g.89333364A>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. 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. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 131 of the POLG protein (p.Tyr131His). This variant is present in population databases (rs562847013, gnomAD 0.04%). This missense change has been observed in individual(s) with mitochondrial myopathy and/or progressive external opthalmoplegia (PMID: 2504279, 16401742, 21880868). ClinVar contains an entry for this variant (Variation ID: 206492). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 12, 2024

Variant summary: POLG c.391T>C (p.Tyr131His) results in a conservative amino acid change located in the DNA mitochondrial polymerase, 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 0.0002 in 186608 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the gnomAD database. c.391T>C has been reported in the literature in the heterozygous state in an individual with clinical features suggestive of POLG deficiency and as a polymorphism in an individual diagnosed with mitochondrial disease who had multiple mtDNA deletions, however no further genotype information was provided (Gonzalez-Vioque_2006, Tang_2011). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. 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: 16401742, 21880868). ClinVar contains an entry for this variant (Variation ID: 206492). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mitochondrial DNA depletion syndrome;C0751964:Primary progressive multiple sclerosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jan 28, 2016

- -

POLG-Related Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

The c.391T>C (p.Y131H) alteration is located in exon 2 (coding exon 1) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 391, causing the tyrosine (Y) at amino acid position 131 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.02% (43/217988) total alleles studied. The highest observed frequency was 0.037% (35/94380) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Mitochondrial disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

A heterozygous missense variant was identified, NM_002693.2(POLG):c.391T>C in exon 2 of 23 of the POLG gene. This substitution is predicted to create a moderate amino acid change from a tyrosine to a histidine at position 131 of the protein, NP_002684.1(POLG):p.(Tyr131His). The tyrosine at this position has low conservation (100 vertebrates, UCSC), and is located within the DNApol exonuclease domain. Pathogenic variants associated with autosomal dominant progressive external ophthalmoplegia are usually located within the finger region of the polymerase domain, whilst variants associated with the autosomal recessive condition are distributed evenly throughout the gene. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.02% (43 heterozygotes, 0 homozygotes). An alternative residue change at the same location, p.(Tyr131Cys), has been reported in the gnomAD database at a frequency of 0.0011%. The variant has been previously reported as a VUS in clinical cases (ClinVar, González-Vioque, E., et al. (2006), Tang, S., et al. (2011)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). -

POLG-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2024

The POLG c.391T>C variant is predicted to result in the amino acid substitution p.Tyr131His. This variant has been reported in two individuals with mitochondrial disease; however, no evidence was provided to determine its pathogenicity (González-Vioque et al. 2006. PubMed ID: 16401742; Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.037% 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. -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.93
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.037	T
ClinPred		0.033	T
GERP RS		2.7

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: rs562847013; hg19: chr15-89876595;