rs147407423

chr15-89325562-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002693.3(POLG):c.1837C>T(p.His613Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,624 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. H613D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 8.13

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05411458).
• BP6: Variant 15-89325562-G-A is Benign according to our data. Variant chr15-89325562-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193643.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Benign=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1837C>T	p.His613Tyr	missense_variant	10/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*1109C>T		3_prime_UTR_variant	10/23
POLG	NM_001126131.2	c.1837C>T	p.His613Tyr	missense_variant	10/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1837C>T	p.His613Tyr	missense_variant	10/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000470 AC: 118 AN: 250954 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135706

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.000492

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: 0.0000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000164 AC: 240 AN: 1461298 Hom.: 1 Cov.: 33 AF XY: 0.000142 AC XY: 103 AN XY: 727000

Gnomad4 AFR exome AF: 0.00457

Gnomad4 AMR exome AF: 0.000648

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: 0.0000261

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74494

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2024	Variant summary: POLG c.1837C>T (p.His613Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 1613624 control chromosomes, predominantly at a frequency of 0.0046 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. c.1837C>T has been reported in the literature in an individual with features POLG-Related Spectrum Disorders (Pozzo_2017). This report does not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28130605). ClinVar contains an entry for this variant (Variation ID: 193643). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2015	- -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2023	Reported as a variant of uncertain clinical significance in two unrelated individuals with clinical features suggestive of POLG deficiency who were heterozygous for p.(H613Y) and did not have another identifiable POLG variant (Tang et al., 2011; Da Pozzo et al., 2017). One individual inherited the p.(H613Y) variant from an apparently unaffected father (Da Pozzo et al., 2017).; 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: 32019516, 28130605, 28480171, 26934580, 25356899, 28569743, 30814510, 25032700, 21880868) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2023	BS1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 13, 2022	- -

Progressive sclerosing poliodystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, 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.1837C>T (NP_002684.1:p.His613Tyr) [GRCH38: NC_000015.10:g.89325562G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

Global developmental delay Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 06, 2020

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2018

The p.H613Y variant (also known as c.1837C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at nucleotide position 1837. The histidine at codon 613 is replaced by tyrosine, an amino acid with similar properties. This alteration was found in the heterozygous state in an individual with ptosis, myopathy, severe cerebellar atrophy, dysarthria, and mild cognitive impairment; and it was inherited from his healthy father (Da Pozzo P et al. Neurol. Sci., 2017 Apr;38:563-570). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

POLG NM_002693.2 exon 10 p.His613Tyr (c.1837C>T): This variant has been reported in the literature in at least two individuals with clinical features of POLG related disease (Tang 2011 PMID:21880868, Da Pozzo 2017 PMID:28130605) and has been identified by our laboratory in at least two individuals with epilepsy. This variant is present in 0.5% (134/24022) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89868793-G-A), and it is present in ClinVar (Variation ID:193643). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. However, the variant Tyrosine (Tyr) amino acid is present in 2 other species (Chinese Softshell Turtle, Spiny Softshell Turtle), suggesting that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

POLG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.15	T;T
Sift4G	Benign	0.29	T;T
Polyphen		1.0	D;D
Vest4		0.92
MVP		0.93
MPC		0.22
ClinPred		0.089	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.63
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs147407423; hg19: chr15-89868793;