15-89330241-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong

The NM_002693.3(POLG):c.695G>A(p.Arg232His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,638 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.76

Publications

10 publications found

Variant links:

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 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-89330242-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 379796.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 15-89330241-C-T is Pathogenic according to our data. Variant chr15-89330241-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.695G>A	p.Arg232His	missense_variant	Exon 3 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5
POLG	NM_001126131.2 link	c.695G>A	p.Arg232His	missense_variant	Exon 3 of 23		NP_001119603.1	P54098E5KNU5
POLGARF	NM_001430120.1 link	c.750G>A	p.Ala250Ala	synonymous_variant	Exon 2 of 2		NP_001417049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.695G>A	p.Arg232His	missense_variant	Exon 3 of 23	1	NM_002693.3	ENSP00000268124.5		P54098
POLGARF	ENST00000706918.1 link	c.750G>A	p.Ala250Ala	synonymous_variant	Exon 2 of 2			ENSP00000516626.1		A0A3B3IS91

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248466

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460404

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111964

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome

Pathogenic:1

Dec 12, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: POLG c.695G>A (p.Arg232His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248466 control chromosomes (gnomAD). c.695G>A has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (e.g. Gui_2015, Hunter_2011, Kuster_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in reduced holoenzyme activity (Lee_2010). The following publications have been ascertained in the context of this evaluation (PMID: 25585994, 20513922, 28924877, 22000311). ClinVar contains an entry for this variant (Variation ID: 21319). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Nov 22, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a reduction in DNA processivity and polymerase gamma holoenzyme steady state levels (PMID: 20513922, 26095671); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25585994, 23430834, 20301791, 18828154, 22237560, 23921535, 17088268, 26095671, 16896309, 18195151, 22000311, 27538604, 27475922, 26056153, 24508722, 32391929, 36732629, 34986040, 38754044, 38975049, 28471437, 20513922) -

Progressive sclerosing poliodystrophy

Pathogenic:1

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the POLG protein (p.Arg232His). This variant is present in population databases (rs113994093, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16896309, 18195151, 18828154, 22000311, 25585994, 27538604, 28471437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant POLG-related conditions (PMID: 23921535); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 21319). 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 80%. Experimental studies have shown that this missense change affects POLG function (PMID: 20513922, 26095671). This variant disrupts the p.Arg232 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 15689359), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial disease

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

7.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.86

Sift

Benign

0.055

T;T

Sift4G

Benign

0.097

T;T

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.81

Loss of phosphorylation at S234 (P = 0.0703);Loss of phosphorylation at S234 (P = 0.0703);

MVP

0.99

MPC

0.44

ClinPred

0.72

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.66

gMVP

0.72

Mutation Taster

=15/85

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over