rs1356604153

chr15-89321253-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_002693.3(POLG):c.2606G>A(p.Arg869Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,794 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). Synonymous variant affecting the same amino acid position (i.e. R869R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.57

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002693.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 15-89321253-C-T is Pathogenic according to our data. Variant chr15-89321253-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436357.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.2606G>A	p.Arg869Gln	missense_variant	17/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1878G>A		3_prime_UTR_variant	17/23
POLG	NM_001126131.2	c.2606G>A	p.Arg869Gln	missense_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.2606G>A	p.Arg869Gln	missense_variant	17/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461794 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive sclerosing poliodystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 869 of the POLG protein (p.Arg869Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Autosomal recessive POLG-related conditions (PMID: 19578034, 21880868, 30818899, 31130284, 31665838). 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: 436357). 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%. For these reasons, this variant has been classified as Pathogenic. -
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.2606G>A (NP_002684.1:p.Arg869Gln) [GRCH38: NC_000015.10:g.89321253C>T] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM1:This variant is in mutational hot spot or a well-studied functional domain without benign variation. 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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	Baylor Genetics	Feb 27, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.88
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.74

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

Other links and lift over

dbSNP: rs1356604153; hg19: chr15-89864484;