rs1085307741

Positions:

• chr15-89317446-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3 PM3_Strong PM2

This summary comes from the ClinGen Evidence Repository: The c.3573 G>T (K1191N) variant in POLG is absent in population databases (PM2 met). Computational prediction tool Revel score 0.876 (PP3 met Revel score > 0.75). This variant has been seen in 3 cases as compound heterozygotes. Two cases with Ala467Thr presenting with Alpers syndrome and one with c.752 C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID:16621917; PMID:21880868; PMID:19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in a autosomal recessive manner.ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10602282/MONDO:0044970/014

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLG ENST00000268124.11 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 0.787

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]

POLGARF (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.3573G>T	p.Lys1191Asn	missense_variant	22/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.*2845G>T		3_prime_UTR_variant	22/23		NP_001393486.1
POLG	NM_001126131.2	c.3573G>T	p.Lys1191Asn	missense_variant	22/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3573G>T	p.Lys1191Asn	missense_variant	22/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	POLG: PM3:Very Strong, PM2, PM5, PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 07, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30423451, 16621917, 21038416, 21880868, 19538466, 24508722) -

Progressive sclerosing poliodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2022	ClinVar contains an entry for this variant (Variation ID: 426681). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 16621917, 19538466, 30423451). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1191 of the POLG protein (p.Lys1191Asn). 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. -
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.3573G>T (NP_002684.1:p.Lys1191Asn) [GRCH38: NC_000015.10:g.89317446C>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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. -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

May 06, 2021

The c.3573G>T (p.K1191N) variant in POLG is absent in population databases (PM2). Computational prediction tool Revel score 0.876 (PP3 met - Revel score > 0.75). This variant has been seen in 3 cases in the compound heterozygote state: in two cases, with Ala467Thr presenting with Alpers syndrome, and one with c.752C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3. -

POLG-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2023

The POLG c.3573G>T variant is predicted to result in the amino acid substitution p.Lys1191Asn. This variant has been reported in the compound heterozygous state with the pathogenic variant p.Ala467Thr or a pathogenic complex allele p.[Thr251Ile;Pro587Leu] in individuals with POLG-related disorders (Horvath et al. 2006. PubMed ID: 16621917; Müller-Höcker et al. 2011. PubMed ID: 19538466; Piekutowska-Abramczuk et al. 2018. PubMed ID: 30423451; Table S2, Kierdaszuk et al. 2021. PubMed ID: 33396418). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as likely pathogenic by the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/426681/). We interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.95		Loss of methylation at K1191 (P = 0.0171);Loss of methylation at K1191 (P = 0.0171);
MVP		0.97
MPC		0.71
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.94
gMVP		0.95

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

Other links and lift over

dbSNP: rs1085307741; hg19: chr15-89860677;