rs61752783

Positions:

• chr15-89326947-C-A
• chr15-89326947-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_002693.3(POLG):​c.1550G>T​(p.Gly517Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,614,202 control chromosomes in the GnomAD database, including 35 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. G517E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (35 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:19 O:1
• Conservation: PhyloP100: 0.623

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:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 15-89326947-C-A is Benign according to our data. Variant chr15-89326947-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65665.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=8, not_provided=1, Uncertain_significance=3}. Variant chr15-89326947-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 35 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1550G>T	p.Gly517Val	missense_variant	8/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*822G>T		3_prime_UTR_variant	8/23
POLG	NM_001126131.2	c.1550G>T	p.Gly517Val	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1550G>T	p.Gly517Val	missense_variant	8/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 772 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00748

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00477 AC: 1198 AN: 251372 Hom.: 3 AF XY: 0.00482 AC XY: 655 AN XY: 135874

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00361

Gnomad NFE exome AF: 0.00751

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00647 AC: 9456 AN: 1461866 Hom.: 35 Cov.: 34 AF XY: 0.00621 AC XY: 4515 AN XY: 727232

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00517

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00425

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.00608

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00477 AC XY: 355 AN XY: 74488

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00748

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00650 Hom.: 0

Bravo AF: 0.00512

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.00474 AC: 576

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:19 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	POLG: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Progressive sclerosing poliodystrophy Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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.1550G>T (NP_002684.1:p.Gly517Val) [GRCH38: NC_000015.10:g.89326947C>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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). 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 Benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2018	The c.1550G>T (p.Gly517Val) variant is classified as likely benign due to its fr equency in the general population. This variant has been identified in 0.73% (92 5/126620) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/), including 3 homozygotes. In addition, function al studies demonstrate an effect indistinguishable from wild type. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -

Idiopathic camptocormia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Department of Neurology, University Hospital of Strasbourg

Jan 01, 2012

- -

Tip-toe gait Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Feb 04, 2021

We conducted a clinical examination of patients about toe walking. The POLG c.1550G>T was detected in 2 patients. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

May 18, 2022

POLG NM_002693.2 exon 8 p.Gly517Val (c.1550G>T): This variant is a well reported and controversial variant in the literature, identified in several individuals with POLG related disease in the heterozygous, compound and double heterozygous state, many of which are reported with significantly variable phenotypes (Horvath 2006 PMID:16621917, Wong 2008 PMID:18546365, Tang 2011 PMID:21880868, Staropoli 2012 PMID:22727047, Gailey 2013 PMID:23808377, Woodbridge 2013 PMID:22647225, DaPozzo 2017 PMID:28130605). However, this variant is present in 0.7% (925/126620) of European alleles, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752783). This variant is present in ClinVar with multiple different classifications, including several Likely Benign/Benign entries (Variation ID:65665). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In addition, functional studies suggest that this variant retains 80-90% of activity relative to wild-type (Kasiviswanathan 2011 PMID:21856450). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is too conflicting for disease classification. Therefore, the clinical significance of this variant is uncertain. -

POLG-Related Spectrum Disorders Benign:1

Likely benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 22, 2021

- -

POLG-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Mitochondrial disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Benign	0.50
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.55	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.28	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0030	B;B
Vest4		0.37
MVP		0.80
MPC		0.19
ClinPred		0.0011	T
GERP RS		1.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.029
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61752783; hg19: chr15-89870178; COSMIC: COSV99074373; COSMIC: COSV99074373;