rs145843073

chr15-89327198-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

The NM_002693.3(POLG):c.1402A>G(p.Asn468Asp) 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 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. N468S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:16 B:1
• Conservation: PhyloP100: 2.97

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 2 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, 8 uncertain in NM_002693.3
• PP5: Variant 15-89327198-T-C is Pathogenic according to our data. Variant chr15-89327198-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=15, Likely_pathogenic=4, Pathogenic=1, Likely_benign=1}. Variant chr15-89327198-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.024409533).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1402A>G	p.Asn468Asp	missense_variant	7/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*674A>G		3_prime_UTR_variant	7/23
POLG	NM_001126131.2	c.1402A>G	p.Asn468Asp	missense_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1402A>G	p.Asn468Asp	missense_variant	7/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000473 AC: 119 AN: 251488 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000829 AC: 1212 AN: 1461886 Hom.: 1 Cov.: 34 AF XY: 0.000792 AC XY: 576 AN XY: 727244

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000920

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000738 AC XY: 55 AN XY: 74500

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000658 Hom.: 0

Bravo AF: 0.000695

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000927

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:16 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	POLG: PM2:Supporting, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2023	Identified in three members of a family with CPEO, peripheral neuropathy, parkinsonism, and multiple mtDNA deletions in muscle who were also heterozygous for another POLG variant on the other allele; the authors could not conclusively determine whether p.(N468D) was related to the phenotype as siblings carrying p.(N468D) were unaffected (Luoma Pet al., 2004; Wanrooij S et al., 2004); Identified as homozygous in an infant with Aicardi-Goutires syndrome who was also homozygous for a pathogenic variant in TREX (Tise CG et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24122062, 19578034, 24508722, 28284481, 31669236, 32391929, 32347949, 29029963, 29712893, 16401742, 24259288, 21880868, 34426522, 22647225, 23811324, 19752458, 15181170, 32234506, 33513296, 23921535, 35114397, 36291626, 15351195, 33683010, 35641312) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 12, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 20, 2022	PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2018	- -

Progressive sclerosing poliodystrophy Pathogenic:2 Benign:1

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.1402A>G (NP_002684.1:p.Asn468Asp) [GRCH38: NC_000015.10:g.89327198T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15351195 ; 16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. PS4:Prevalence of variant in affecteds statistically increased over controls. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 27, 2023	- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 04, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 24, 2022	- -

Progressive sclerosing poliodystrophy;C3150914:Mitochondrial DNA depletion syndrome 4b Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: POLG c.1402A>G (p.Asn468Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251488 control chromosomes (119/251488 control chromosomes). c.1402A>G has been reported in the literature in individuals affected with variety of POLG-related phenotypes. The variant has been reported in three affected family members (and no unaffected family members) with progressive external ophthalmoplegia and parkinsonism as well as a patient with early onset Parkinson's disease, all with a second variant of unknown significance (Luoma_2004, Ylonen_2017). Additionally, the variant was reported along with a pathogenic variant in cases of progressive external ophthalmoplegia and tetraparesis and mitochondrial neurogastrointestinal encephalopathy (Gonzalez-Vioque_2006, Woodbridge_2013). The variant has also been reported in the homozygous state in a patient with congenital ataxia who had no features suggestive of a POLG-related phenotype, therefore ITPR1 variants were considered resposible for congenital ataxia in this patient (Valence_2019). These data indicate that the variant is likely to be associated with disease. 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: 31658717, 16401742, 15351195, 15181170, 22647225, 29029963, 29997391). 19 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 submitters classified the variant as LP/P, 1 as LB and 15 as VUS). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

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 31, 2018

- -

POLG-Related Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 01, 2021

The POLG c.1402A>G; p.Asn468Asp variant is reported in the literature in individuals affected with autosomal recessive progressive external ophthalmoplegia (Luoma 2004, Palin 2013, Woodbridge 2013). The affected individuals identified in these reports were compound heterozygous for the p.Asn468Asp variant while heterozygous carriers in the same family were unaffected. The variant has also been shown to co-segregate with disease in families with autosomal recessive progressive external ophthalmoplegia (Wanrooij 2004). This variant is reported with conflicting interpretations in ClinVar (Variation ID: 206596). Another variant in this region, p.Ala467Thr, is considered the most common pathogenic POLG variant (Variation ID: 13496). However, due to limited functional evidence, the clinical significance of the p.Asn468Asp variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2022

The c.1402A>G (p.N468D) alteration is located in exon 7 (coding exon 6) of the POLG gene. This alteration results from a A to G substitution at nucleotide position 1402, causing the asparagine (N) at amino acid position 468 to be replaced by an aspartic acid (D). The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.N468 amino acid is not conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.N468D alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lennox-Gastaut syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

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

Dec 05, 2016

- -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

Seizure;C3714756:Intellectual disability Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 07, 2020

- -

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 7 p.Asn468Asp (c.1402A>G): This variant has been reported in the literature in the compound heterozygous state in at least 3 individuals with autosomal recessive progressive external opthalmoplegia in addition to ataxia, tetraparesis, and/or parkinsonism, segregating with disease in two affected family members (Luoma 2004 PMID:15351195, Gonzalez-Viogue 2006 PMID:16401742, Woodbridge 2013 PMID:22647225). This variant has also been identified in multiple individuals with suspected POLG-deficiency who did not have a second identifiable variant in the POLG gene (Blok 2009 PMID:19578034, Tang 2011 PMID:21880868). This variant is present in 0.07% (18/25122) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89870429-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:206596). This variant amino acid Aspartic Acid (Asp) is present in several species including two mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. 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	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	17
Dann	Benign	0.42
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.95	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.24
Sift	Benign	0.72	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.44
MVP		0.84
MPC		0.18
ClinPred		0.0045	T
GERP RS		2.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.15
gMVP		0.22

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: rs145843073; hg19: chr15-89870429;