rs11546842

chr15-89320890-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_002693.3(POLG):c.2857C>T(p.Arg953Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging 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. R953H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 9.60

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:):

POLGARF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002693.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-89320889-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 619427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 15-89320890-G-A is Pathogenic according to our data. Variant chr15-89320890-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194838.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.2857C>T	p.Arg953Cys	missense_variant	18/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2129C>T		3_prime_UTR_variant	18/23
POLG	NM_001126131.2 linkuse as main transcript	c.2857C>T	p.Arg953Cys	missense_variant	18/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.2857C>T	p.Arg953Cys	missense_variant	18/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251172

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00

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:

0.0000649

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Observed with a pathogenic variant in an adult with peripheral neuropathy, ophthalmoparesis/CPEO, ptosis, COX deficiency, ragged-red fibers, migraines, diarrhoea, lactic acidosis, hypotonia, ataxia, seizures, exercise intolerance, muscle weakness, muscle cramps, optic atrophy, and easy fatigability, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Tang et al., 2011); Reported in an individual with adult onset PEO, ptosis, muscle weakness, hypothyreosis, ataxia, asthma and balance disturbance; however, information on the zygosity of the variant was not provided and parental studies were not performed (Luoma et al., 2004); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25203713, 24122062, 20185557, 21880868, 22334187, 15351195, 20701905, 28480171, 25724872, 21993618, 35114397, 31665838, 33434755, Crawford2022[casereport], 27381400, 22617125, 27748512, 22334185, 29992832, 18321754, 33513296) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 18, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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. Computational tools predict that this variant is damaging. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	POLG: PM2, PM3, PP1:Moderate, PP3 -

Progressive sclerosing poliodystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 17, 2023	- -
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.2857C>T (NP_002684.1:p.Arg953Cys) [GRCH38: NC_000015.10:g.89320890G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 953 of the POLG protein (p.Arg953Cys). This variant is present in population databases (rs11546842, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive progressive external ophthalmoplegia (PMID: 21880868, 22334187, 33046616). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 194838). 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%. Experimental studies have shown that this missense change does not substantially affect POLG function (PMID: 20185557). This variant disrupts the p.Arg953 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 31665838), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

May 04, 2021

- -

POLG-Related Spectrum Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 10, 2023

Variant summary: POLG c.2857C>T (p.Arg953Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. This alters a highly conserved residue in which other missense variants have been found in association with disease (HGMD), suggesting this may be a functionally important region of the protein. 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 2.4e-05 in 251172 control chromosomes (gnomAD). c.2857C>T has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders (Gurgel-Giannetti_2012, Luoma_2016, Paul_2020, Tang_2012, Wahbi_2015), and some patients were reported as compound heterozygous with other likely pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. One found that the orthologous variant in yeast did not increase the number of colonies unable to perform aerobic respiration (Stumpf_2010), while another study found that the variant resulted in a sharply reduced efficiency of dCTP incorporation in vitro (Li_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22334187, 15351195, 21993618, 26224072, 20185557, 33046616, 27381400). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1), likely pathogenic (n=4), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.93

MVP

0.99

MPC

0.77

ClinPred

0.90

GERP RS

5.2

Varity_R

0.92

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over