rs139599587

chr15-89333427-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP4

The NM_002693.3(POLG):c.328C>T(p.His110Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000846 in 1,608,446 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). Synonymous variant affecting the same amino acid position (i.e. H110H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 9.59

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 5: BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate [when AlphaMissense, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.26894468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.328C>T	p.His110Tyr	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.383C>T	p.Ala128Val	missense_variant	2/23
POLG	NM_001126131.2	c.328C>T	p.His110Tyr	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.328C>T	p.His110Tyr	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.383C>T	p.Ala128Val	missense_variant	1/2			P1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152274 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 43 AN: 238934 Hom.: 0 AF XY: 0.000183 AC XY: 24 AN XY: 130928

Gnomad AFR exome AF: 0.000781

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000787

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000646 AC: 94 AN: 1456054 Hom.: 1 Cov.: 32 AF XY: 0.0000731 AC XY: 53 AN XY: 724656

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152392 Hom.: 0 Cov.: 34 AF XY: 0.000268 AC XY: 20 AN XY: 74520

Gnomad4 AFR AF: 0.000865

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000906 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000174 AC: 21

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2022	Reported previously in a female with hypotonia, failure to thrive, and short stature who did not have a second detectable variant in the POLG gene (Wong et al., 2008).; Reported previously in the heterozygous state in a child with chronic progressive external ophthalmoplegia and complex I deficiency with no second variant identified; however, segregation information was not provided (Sonam 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: 18546365, 20185557, 33469851, 32348839, 27826120, 28480171, 30214008, 26934580) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -

Progressive sclerosing poliodystrophy Uncertain:1 Benign:1

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.328C>T (NP_002684.1:p.His110Tyr) [GRCH38: NC_000015.10:g.89333427G>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. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BS3:Well-established functional studies show no deleterious effect. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 110 of the POLG protein (p.His110Tyr). This variant is present in population databases (rs139599587, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of POLG-related conditions (PMID: 18546365, 27826120). ClinVar contains an entry for this variant (Variation ID: 206619). 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. Experimental studies have shown that this missense change does not substantially affect POLG function (PMID: 20185557). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 20, 2021

Variant summary: POLG c.328C>T (p.His110Tyr) 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 0.00018 in 238934 control chromosomes (gnomAD). c.328C>T has been reported in the literature in individuals affected with features of Alpers syndrome, chronic progressive external ophthalmoplegia and sensory ataxic neuropathy with cerebellar syndrome (Wong_2008, Sonam_2017, Deepha_2021). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. Experimental evidence evaluating an impact on protein function in yeast assays, demonstrated the variant to function similarly to wild-type (Stumpf_2010). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2019

The p.H110Y variant (also known as c.328C>T), located in coding exon 1 of the POLG gene, results from a C to T substitution at nucleotide position 328. The histidine at codon 110 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in a three year old patient with some features of Alpers syndrome and in an eleven year old girl with CPEO plus syndrome (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72; Sonam K et al. Mitochondrion, 2017 Jan;32:42-49). 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 2 p.His110Tyr (c.328C>T): This variant has been reported in the literature in 1 individual with features of Alpers syndrome (hypotonia, failure to thrive, short stature and respiratory failure) (Wong 2008 PMID:18546365). This variant is present in 0.07% (19/24074) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-89876658-G-A). This variant is present in ClinVar (Variation ID:206619). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Functional studies involving yeast suggest that this variant may not impact the protein (Stumpf 2010 PMID:20185557). However, these studies may not accurately represent human biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.27	T
MutationTaster	Benign	1.0	D;D
ClinPred		0.14	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139599587; hg19: chr15-89876658;