rs113994097

chr15-89323426-C-G

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: POLG NM_002693 missense
• Clinical Significance: Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations P:31 U:1 O:2
• Conservation: PhyloP100: 7.74

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002693
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• PP5: Variant 15:89323426-C>G is Pathogenic according to our data. Variant chr15-89323426-C-G is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 13507. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=20, Uncertain_significance=1, Likely_pathogenic=3}. Variant chr15-89323426-C-G is described in Lovd as [Pathogenic]. Variant chr15-89323426-C-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.082895756).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2243G>C	p.Trp748Ser	missense_variant	13/23	ENST00000268124.11
POLG	NM_001126131.2	c.2243G>C	p.Trp748Ser	missense_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2243G>C	p.Trp748Ser	missense_variant	13/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 113 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000971 AC: 244 AN: 251290 Hom.: 0 AF XY: 0.000987 AC XY: 134 AN XY: 135828

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00601

Gnomad NFE exome AF: 0.000950

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000730 AC: 1066 AN: 1460716 Hom.: 1 AF XY: 0.000736 AC XY: 535 AN XY: 726750

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00631

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.000547

Alfa AF: 0.000506 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting interpretations of pathogenicity

Submissions summary: Pathogenic:31Uncertain:1Other:2

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

not provided Pathogenic:13Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 30, 2021	- -
not provided, no assertion provided	phenotyping only	GenomeConnect, ClinGen	-	Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Jun 24, 2020	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	Criteria applied: PS1, PM1, PP1, PP3, PP4, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Karolinska University Hospital, Karolinska University Hospital	Feb 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	PerkinElmer Genomics	Dec 21, 2020	- -

Progressive sclerosing poliodystrophy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 31, 2022	This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 28, 2022	- -
Pathogenic, 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.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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 expected to disrupt POLG protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:26077851) (PMID:15477547). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:20153822). PS3 => Well-established functional studies show a deleterious effect (PMID:17088268). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2018	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -

POLG-Related Spectrum Disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2018	The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3. -

Mitochondrial DNA depletion syndrome 4b Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Klinikum rechts der Isar	Jul 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jun 10, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4. -

Mitochondrial disease Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	Apr 07, 2017	- -
not provided, no assertion provided	literature only	GeneReviews	-	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 25, 2017

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2018

The p.W748S pathogenic mutation (also known as c.2243G>C), located in coding exon 12 of the POLG gene, results from a G to C substitution at nucleotide position 2243. The tryptophan at codon 748 is replaced by serine, an amino acid with highly dissimilar properties. This variant is a well described founder mutation, accounting for up to 8% of disease causing alleles in the Finnish population. Additionally, this mutation has been described many times in the homozygous and compound heterozygous states in individuals with Alpers-Huttenlocher syndrome (AHS), SANDO, MEMSA, and other autosomal recessive POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, myopathy, tremors, cognitive decline, and hearing loss (Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83; Janssen W et al. Acta Neurol Belg, 2016 Mar;116:17-25; Uusimaa J et al. Epilepsia, 2008 Jun;49:1038-45; Henao AI et al. Neuroradiol J, 2016 Feb;29:46-8; Masingue M et al. Mitochondrion, 2018 Feb; Hikmat O et al. Int J Mol Sci, 2017 Aug;18:). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Spinocerebellar ataxia with epilepsy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.23

D

BayesDel_noAF

Pathogenic

0.49

Cadd

Pathogenic

32

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

D

M_CAP

Uncertain

0.21

D

MetaRNN

Benign

0.083

T;T

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.71

T

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.024

D;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.97

MPC

0.85

ClinPred

0.13

T

GERP RS

5.6

Varity_R

0.90

gMVP

0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113994097; hg19: chr15-89866657;