rs1131691575

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_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 (★★★).

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:8

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:

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FANCI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 rank	MANE	Protein	UniProt
POLG	NM_002693.3 link	c.3550G>A	p.Asp1184Asn	missense_variant	Exon 22 of 23	ENST00000268124.11	NP_002684.1	P54098E5KNU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11 link	c.3550G>A	p.Asp1184Asn	missense_variant	Exon 22 of 23	1	NM_002693.3	ENSP00000268124.5		P54098

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:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mitochondrial disease

Pathogenic:2

Apr 07, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 23, 2021

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 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. ClinVar contains an entry for this variant (Variation ID: 426100). 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 affects POLG function (PMID: 20185557). For these reasons, this variant has been classified as Pathogenic. -

May 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

May 27, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

POLG-related disorder

Pathogenic:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLG c.3550G>A variant is predicted to result in the amino acid substitution p.Asp1184Asn. This variant was reported in the compound heterozygous state in individuals with autosomal recessive progressive external ophthalmoplegia (Blok et al. 2009. PubMed ID: 19578034; Gonzalez-Vioque et al. 2006. PubMed ID: 16401742; Li et al. 2019. PubMed ID: 30678510). This variant affects a highly conserved residue in the polymerase domain in mitochondrial polymerase gamma. In addition, another variant affecting the asparagine 1184 residue has also been reported to cause autosomal recessive PEO when present in trans with a second pathogenic variant (Martikainen et al. 2010. PubMed ID: 22778364). Heterozygous carriers of the POLG c.3550G>A variant have been reported to be asymptomatic (Blok et al. 2009. PubMed ID: 19578034; Li et al. 2019. PubMed ID: 30678510). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89860700-C-T). Taken together, this variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Oct 31, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Pathogenic:1

Jan 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M

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