rs181860632

chr15-89319065-G-Achr15-89319065-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_002693.3(POLG):c.3139C>T(p.Arg1047Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,088 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1047Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:4 O:1
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 11) in uniprot entity DPOG1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_002693.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 15-89319065-G-A is Pathogenic according to our data. Variant chr15-89319065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206548.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Uncertain_significance=4, not_provided=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3139C>T	p.Arg1047Trp	missense_variant	20/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*2411C>T		3_prime_UTR_variant	20/23
POLG	NM_001126131.2	c.3139C>T	p.Arg1047Trp	missense_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.3139C>T	p.Arg1047Trp	missense_variant	20/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251358 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135858

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74400

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20818383, 31571979, 19251978, 22189570, 18195149, 29655203, 32347949, 35186329, 34690748) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with autosomal recessive POLG-related disorders. Computational tools predict that this variant is damaging. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2020	PS4_moderate, PM2, PM3, PM5, PP5 -

Progressive sclerosing poliodystrophy Pathogenic:4

Likely 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.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . This variant meets the following evidence codes reported in the ACMG-guideline. 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 Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1047 of the POLG protein (p.Arg1047Trp). This variant is present in population databases (rs181860632, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 18195149, 22189570). ClinVar contains an entry for this variant (Variation ID: 206548). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLG related disorder (PMID:18195149, PS1_P). A different missense change at the same codon has been reported to be associated with POLG related disorder (PMID:12707443, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.848, 3CNET: 0.788, PP3_P). A missense variant is a common mechanism associated with Progressive external ophthalmoplegia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). . The variant has been reported to be in trans with a pathogenic variant as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 12, 2024

Variant summary: POLG c.3139C>T (p.Arg1047Trp) 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. 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 4e-05 in 251358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.3139C>T has been reported in the literature in compound heterozygous individuals affected with Alpers disease (e.g. Wiltshire_2008) or progressive external ophthalmoplegia (e.g. Stewart_2009), or as a heterozygous genotype in an individual affected with mitochondrial complex I disorder without strong evidence for causality (e.g. Calvo_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20818383, 29655203, 19251978, 18195149). ClinVar contains an entry for this variant (Variation ID: 206548). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.3139C>T (p.R1047W) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the arginine (R) at amino acid position 1047 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C1843852:Spinocerebellar ataxia with epilepsy Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 11-30-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.88
MVP		0.99
MPC		0.67
ClinPred		0.80	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs181860632; hg19: chr15-89862296; COSMIC: COSV51525241; COSMIC: COSV51525241;