rs150233690

chr15-89319073-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_002693.3(POLG):c.3131T>C(p.Val1044Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,614,046 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (2 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16 B:1
• Conservation: PhyloP100: 1.50

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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002693.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.11218697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.3131T>C	p.Val1044Ala	missense_variant	20/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*2403T>C		3_prime_UTR_variant	20/23
POLG	NM_001126131.2	c.3131T>C	p.Val1044Ala	missense_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.3131T>C	p.Val1044Ala	missense_variant	20/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000648 AC: 163 AN: 251418 Hom.: 0 AF XY: 0.000662 AC XY: 90 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000985

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000832 AC: 1217 AN: 1461888 Hom.: 2 Cov.: 32 AF XY: 0.000862 AC XY: 627 AN XY: 727246

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000970

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74332

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000901 Hom.: 1

Bravo AF: 0.000589

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2023	Reported previously in an individual with severe encephalopathy, intractable epilepsy, an athetoid-ataxic movement disorder, and developmental regression, who also harbored a second POLG variant on the opposite allele (Isohanni et al., 2011); please note that this second POLG variant is classified as benign by GeneDx; Reported in a patient with mtDNA depletion syndrome with liver fibrosis and portal hypertension, and two other POLG variants with unknown phase (Stalke et al., 2017); Reported in a child with developmental delay, hypotonia, encephalopathy, seizure, intractable seizure, muscle weakness, gastrointestinal reflux in whom a second POLG variant was not described (Tang et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21357833, 28337550, 28776642, 21880868, 34426522, Singh2021[Poster], 32391929) -

Progressive sclerosing poliodystrophy Uncertain:1 Benign:1

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.3131T>C (NP_002684.1:p.Val1044Ala) [GRCH38: NC_000015.10:g.89319073A>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:21357833 . This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 30, 2023

Variant summary: POLG c.3131T>C (p.Val1044Ala) 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. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders (0.00065 vs 0.0035), allowing no conclusion about variant significance. c.3131T>C has been reported in the literature as a compound heterozygous genotype in an individual with an Alpers-like phenotype (Isohanni_2011), in the heterozygous state together with other POLG variants (phase unspecified) in an individual suspected of an atypical mitochondrial DNA depletion syndrome presenting with liver fibrosis with portal hypertension (Stalke_2018), and as an uninformative genotype (i.e. zygosity not specified) in at least one individual from a cohort of patients with POLG-related disorders (Hkitmat_2020). It has also been reported in a case-control study in two individuals affected with multiple sclerosis, but was also found in one control individual (Traboulsee_2017). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 32391929, 21357833, 28776642, 28337550). Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS, and one submitter classified it as likely benign. 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

May 03, 2022

- -

POLG-Related Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 15, 2018

The POLG c.3131T>C (p.Val1044Ala) has been reported in four studies and in a total of five patients including one in a compound heterozygous state, and four in a heterozygous state (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). Two of the individuals identified with the variant have multiple sclerosis, two have mitochondrial disease, and the fifth was noted to have POLG-deficiency (Isohanni et al. 2011; Tang et al. 2011; Stalke et al. 2018; Traboulsee et al. 2017). The p.Val1044Ala variant was found in one control out of 1200 control individuals and is reported at a frequency of 0.003319 in the Other population of the Exome Aggregation Consortium. Based on the evidence, the p.Val1044Ala is classified as a variant of unknown significance, but suspicious for pathogenicity for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.3131T>C (p.V1044A) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 3131, causing the valine (V) at amino acid position 1044 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2018

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C3150914:Mitochondrial DNA depletion syndrome 4b Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

May 27, 2021

- -

Early-onset Parkinson disease 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 15, 2020

- -

EEG abnormality Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	9.6
Dann	Benign	0.93
DEOGEN2	Uncertain	0.67	D;D
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.61
Sift	Benign	0.44	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0080	B;B
Vest4		0.39
MVP		0.86
MPC		0.20
ClinPred		0.0062	T
GERP RS		0.072
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.54

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: rs150233690; hg19: chr15-89862304;