rs202037973

chr15-89323423-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_002693.3(POLG):c.2246T>C(p.Phe749Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F749V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 7.20

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 Uncertain_significance. Variant got 5 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_002693.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 15-89323423-A-G is Pathogenic according to our data. Variant chr15-89323423-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206520.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=8, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2246T>C	p.Phe749Ser	missense_variant	13/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1518T>C		3_prime_UTR_variant	13/23
POLG	NM_001126131.2	c.2246T>C	p.Phe749Ser	missense_variant	13/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2246T>C	p.Phe749Ser	missense_variant	13/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251288 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135832

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1460476 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726616

Gnomad4 AFR exome AF: 0.000957

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74422

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000516 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive sclerosing poliodystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 749 of the POLG protein (p.Phe749Ser). This variant is present in population databases (rs202037973, gnomAD 0.07%). This missense change has been observed in individuals with Alpers syndrome, autosomal recessive progressive external ophthalmoplegia, and/or seizures (PMID: 16545482, 18716558, 21670405, 21880868, 28865037). ClinVar contains an entry for this variant (Variation ID: 206520). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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.2246T>C (NP_002684.1:p.Phe749Ser) [GRCH38: NC_000015.10:g.89323423A>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 ; 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. -

POLG-Related Spectrum Disorders Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 15, 2023	Variant summary: POLG c.2246T>C (p.Phe749Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251288 control chromosomes. c.2246T>C has been reported in the literature in multiple compound heterozygous individuals carrying additional pathogenic variants affected with clinical features of POLG-related disorders (examples: Tang_2011, Milone_2011, Zsurka_2008), including reduced mitochondrial enzyme activity (Zsurska_2008), and in Alpers syndrome (examples: Hikmat_2017, Nguyen_2006). These data indicate that the variant is very likely to be associated with disease. Two publications report predictive evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (examples: Euro_2011, Zsurska_2008). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=2), likely pathogenic (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 26, 2019	The POLG c.2246T>C (p.Phe749Ser) variant is a missense variant that has been reported in four studies, in which it is found in a compound heterozygous state in a total of six individuals, including in three with POLG deficiency, in one with autosomal recessive POLG-related disorders, in one with Alpers syndrome, and in one with some features of the Alpers-Huttenlocher syndrome (Nguyen et al. 2006; Zsurka et al. 2008; Milone et al. 2011; Tang et al. 2011). The p.Phe749Ser variant was absent from 100 control subjects and is reported at a frequency of 0.000681 in the African population of the Genome Aggregation Database. The p.Phe749Ser variant demonstrated reduced mitochondrial DNA copy numbers in patient blood and tissue samples (Zsurka et al. 2008). Muscle biopsies from the Alpers-Huttenlocher syndrome patient revealed large mtDNA deletions, however, the mitochondrial impairment in the muscle tissue could not be explained solely by deletions (Zsurka et al. 2008). The phe749 residue is in the linker region suggested to be involved in protein–protein interactions but is not critical for catalytic function of the enzyme (Euro et al. 2011). Based on the collective evidence, the p.Phe749Ser variant is classified as likely pathogenic for POLG-related spectrum disorders. -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 25, 2022	The c.2246T>C;p.(Phe749Ser) missense change has been observed in affected individual(s) PMID: 24642831; PMID: 21880868; PMID: 21670405)-PS4_moderate. The variant is present at low allele frequencies population databases (rs202037973 – gnomAD 0.0006368%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Phe749Ser) was detected in trans with a pathogenic variant (PMID: 21880868; PMID: 21670405) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17538929, 21824913, 23446635, 32347949, 34777884, 21670405, 17280874, 21880868, 16545482, 18716558, 21953457, 19195941, 24642831, 17682973, 32391929, Alghtani_Article, 28206745, 35289132, 36510129) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 23, 2020	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. 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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.2246T>C (p.F749S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 2246, causing the phenylalanine (F) at amino acid position 749 to be replaced by a serine (S). Based on the supporting evidence, this alteration is classified as likely pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the C allele has an overall frequency of 0.01% (18/282674) total alleles studied. The highest observed frequency was 0.07% (17/24960) of African alleles. This alteration has been identified in the compound heterozygous state in individuals exhibiting a range a phenotypes associated with autosomal recessive POLG-related mitochondrial disorders (Milone, 2011; Nguyen, 2006; Tang, 2011; Zsurka, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

POLG-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

The POLG c.2246T>C variant is predicted to result in the amino acid substitution p.Phe749Ser. This variant has previously been reported in the compound heterozygous state in patients who presented with POLG-associated disorders, including Alpers syndrome, progressive external ophthalmoplegia (PEO), and intractable seizures (Nguyen et al. 2006. PubMed ID: 16545482; Zsurka et al. 2008. PubMed ID: 18716558; Milone et al. 2011. PubMed ID: 21670405; Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89866654-A-G). This variant is interpreted as likely pathogenic. -

Seizure;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Mar 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.95
MPC		0.89
ClinPred		0.75	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.94

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: rs202037973; hg19: chr15-89866654;