Genetic Variant NM_002693.3:c.1760C>T (chr15-89325639-G-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM1PP3PP5BP4

The NM_002693.3(POLG):c.1760C>T(p.Pro587Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,612,514 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002556643: Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P587P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:48U:5O:2

Conservation

PhyloP100: 10.0

Publications

88 publications found

Variant links:

COSMIC-nc: COSV105090786

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]

POLG Gene-Disease associations (from GenCC):

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
mitochondrial DNA depletion syndrome 4a
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
autosomal dominant progressive external ophthalmoplegia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive progressive external ophthalmoplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial neurogastrointestinal encephalomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
recessive mitochondrial ataxia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
spinocerebellar ataxia with epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

POLG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002556643: Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3).; SCV000886904: "Well established functional studies show a deleterious effect on POLG."; SCV005088880: "individually both p.Thr251Ile and p.Pro587Leu substitutions functionally impair pol γ activity." PMID:28154168; SCV005398490: Studies show that this variant reduces thermostability and impairs catalytic activity. The dysfunction is more severe when the variant is in cis with p.(Thr251Ile) (PMID: 28154168).; SCV004801567: DeBalsi et al. (2017) investigated the biochemical properties of purified recombinant Pol gamma p.Pro587Leu protein expressed using the baculovirus Sf9 system. Experiments demonstrated that the p.Pro587Leu variant caused a two-fold reduction in DNA binding affinity and significantly reduced thermostability. The catalytic efficiency of the p.Pro587Leu protein was reduced to approximately 32% of the wildtype level.; SCV000847670: "Biochemical characterization of P587L mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than P587L alone (DeBalsi, 2017)."; SCV004229435: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 33579567, 28154168)

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_002693.3

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 15-89325639-G-A is Pathogenic according to our data. Variant chr15-89325639-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13505.

BP4

Computational evidence support a benign effect (MetaRNN=0.090871036). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.1760C>T	p.Pro587Leu	missense	Exon 10 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.1760C>T	p.Pro587Leu	missense	Exon 10 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLG	ENST00000268124.11	TSL:1 MANE Select	c.1760C>T	p.Pro587Leu	missense	Exon 10 of 23	ENSP00000268124.5	P54098
POLG	ENST00000442287.6	TSL:1	c.1760C>T	p.Pro587Leu	missense	Exon 10 of 23	ENSP00000399851.2	P54098
POLG	ENST00000636937.2	TSL:5	c.1760C>T	p.Pro587Leu	missense	Exon 10 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00155

AC:

386

AN:

249778

AF XY:

0.00158

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000344

Gnomad NFE exome

AF:

0.00270

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00203

AC:

2969

AN:

1460200

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1433

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.000850

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000371

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000521

AC:

AN:

51788

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00244

AC:

2710

AN:

1111968

Other (OTH)

AF:

0.00171

AC:

103

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

169

337

506

674

843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152314

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41564

American (AMR)

AF:

0.00104

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00256

AC:

174

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00220

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00170

AC:

206

EpiCase

AF:

0.00256

EpiControl

AF:

0.00308

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (16)

Progressive sclerosing poliodystrophy (9)

POLG-related disorder (5)

Mitochondrial DNA depletion syndrome 4b (4)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (4)

Mitochondrial disease (3)

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b (2)

Abnormality of the nervous system (1)

Global developmental delay (1)

Hereditary spastic paraplegia (1)

Hypertrophic cardiomyopathy (1)

Inborn genetic diseases (1)

Mitochondrial DNA depletion syndrome 1 (1)

not specified (1)

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.091

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PhyloP100

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.66

MVP

0.97

MPC

0.66

ClinPred

0.071

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.79

gMVP

0.73

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over