rs1131691575

Positions:

chr15-89317469-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002693.3(POLG):c.3550G>A(p.Asp1184Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,976 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. D1184G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 7.57

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_002693.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-89317468-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1957072.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 15-89317469-C-T is Pathogenic according to our data. Variant chr15-89317469-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 426100.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLG	NM_002693.3 linkuse as main transcript	c.3550G>A	p.Asp1184Asn	missense_variant	22/23	ENST00000268124.11
POLGARF	NM_001406557.1 linkuse as main transcript	c.*2822G>A		3_prime_UTR_variant	22/23
POLG	NM_001126131.2 linkuse as main transcript	c.3550G>A	p.Asp1184Asn	missense_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11 linkuse as main transcript	c.3550G>A	p.Asp1184Asn	missense_variant	22/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152152

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

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251494

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000612

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mitochondrial disease

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	Apr 07, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	May 23, 2021	The c.3550 G>A (p.Asp1184Asn) variant in POLG has been reported in gnomAD in 0.0001% allele frequency with no homozygotes (PM2). There is also multiple other pathogenic variants at the same amino acid residue as well as nearby: Asp1184His, Ile1185Thr, Ile1185Asn, Asp1186His, and Cys1188Arg all have been reported in the Human Gene Mutation Database in association with POLG-related disorders (PS1; PMID 24077912). There are 5 cases reported with POLG related disease symptoms PEO, neurological phenotype, liver issues, and epilepsy. These cases are reported in 2 compound heterozygotes with c.679 C>T; p.Arg227Trp, a compound heterozygote with c.752 C>T; p.Thr251Ile and c.1759 C>T; p.Pro587Leu; a compound heterozygote with c.3285 C>G; p.Ser1095Arg (PM3_strong; PMID:16957900; PMID:30678510; PMID:19344718; PMID:19578034).There is 1 additional case in the literature as a compound heterozygotes however there is conflicting evidence of pathogenicity of the variant. Therefore this case could not be counted (PMID: 16401742). In summary, this variant meets criteria to be classified as pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PS1, PM2, PM3_strong -

Progressive sclerosing poliodystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 27, 2023	ClinVar contains an entry for this variant (Variation ID: 426100). This missense change has been observed in individuals with autosomal recessive POLG-related disorders (PMID: 16401742, 16957900, 19578034, 30678510). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1184 of the POLG protein (p.Asp1184Asn). 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 06, 2023	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The c.3550G>A (p.D1184N) alteration is located in exon 22 (coding exon 21) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 3550, causing the aspartic acid (D) at amino acid position 1184 to be replaced by an asparagine (N). Based on data from the Genome Aggregation Database (gnomAD) database, the POLG c.3550G>A alteration was observed in 0.001% (3/282,882) of total alleles studied, with a frequency of 0.003% (1/35,440) in the Latino subpopulation. This alteration has been previously reported in multiple patients with autosomal recessive POLG-related mitochondrial disorders, including progressive external ophthalmoplegia (arPEO) (Gonzalez-Vioque, 2006; de Vries, 2007; Blok, 2009; Li, 2019). This amino acid position is highly conserved in available vertebrate species. Functional studies using yeast mtDNA point mutagenesis with p.D1184N (yeast ortholog D941N) showed an increased petite colony formation frequency and exhibited decreased mtDNA copy number, suggesting that mtDNA depletion is a major phenotype of this disease-associated mutant (Stumpf, 2010). The in silico prediction for the p.D1184N alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2018

The D1184N variant in the POLG gene has been reported previously in multiple unrelated individuals with POLG-related disorders who had a second POLG variant identified (de Vries et al., 2007; Amiot et al., 2009; Blok et al., 2009). Functional studies show that D1184N results in mtDNA depletion as well as increased petite colony formation, suggesting it may be a null variant (Stumpf et al., 2010). The D1184N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1184N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and a different missense variant in the same residue (D1184H) as well as missense variants in nearby residues (I1185T, I1185N, D1186H, C1188R) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, D1184N is considered a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.2

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.88

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.99

MPC

0.65

ClinPred

0.99

GERP RS

6.0

Varity_R

0.60

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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