rs121918052

chr15-89327006-C-Gchr15-89327006-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_002693.3(POLG):c.1491G>C(p.Gln497His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q497Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:7
• Conservation: PhyloP100: 2.27

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42042285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1491G>C	p.Gln497His	missense_variant	8/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*763G>C		3_prime_UTR_variant	8/23
POLG	NM_001126131.2	c.1491G>C	p.Gln497His	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1491G>C	p.Gln497His	missense_variant	8/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251486 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.0000536 AC XY: 39 AN XY: 727236

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: 0.000112

Gnomad4 NFE exome AF: 0.0000674

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Aug 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	To our knowledge, Q497H has not been reported as an independent disease-causing mutation causing POLG-related disorders when in the homozygous state or in trans with a second variant. Q497H is a non-conservative amino acid substitution of a neutral, polar Glutamine with a positively charged Histidine at a residue that is conserved across mammalian species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The Q497H variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q497H as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -

Progressive sclerosing poliodystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 21, 2023	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 497 of the POLG protein (p.Gln497His). This variant is present in population databases (rs121918052, gnomAD 0.03%). This missense change has been observed in individual(s) with POLG-related conditions (PMID: 15824347, 18546365, 18991199, 21357833, 25025039, 25065347, 26942291). ClinVar contains an entry for this variant (Variation ID: 13510). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, 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.1491G>C (NP_002684.1:p.Gln497His) [GRCH38: NC_000015.10:g.89327006C>G] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:1582434 . This variant meets the following evidence codes reported in the ACMG-guideline. BP2:The variant is observed in trans/cis with a dominant variant. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -

Spinocerebellar ataxia with epilepsy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 12, 2005

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 25, 2023

Variant summary: POLG c.1491G>C (p.Gln497His) results in a non-conservative amino acid change in 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 0.00013 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (0.00013 vs 0.0035), allowing no conclusion about variant significance. c.1491G>C has been reported in the literature in individuals affected with POLG-Related conditions who carried other variants in cis as well as pathogenic variants in trans. These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. 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: 15824347, 33726816, 18546365, 25025039, 32391929, 18991199, 26942291, 21357833, 25065347). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.98	D;D
Vest4		0.53
MutPred		0.74		Loss of disorder (P = 0.0978);Loss of disorder (P = 0.0978);
MVP		0.95
MPC		0.58
ClinPred		0.23	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.46

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: rs121918052; hg19: chr15-89870237;