rs113994095

chr15-89327201-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM5 PP5_Very_Strong

The NM_002693.3(POLG):c.1399G>A(p.Ala467Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,614,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A467D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:48 O:2
• Conservation: PhyloP100: 7.47

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 Pathogenic. Variant got 12 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, 9 uncertain in NM_002693.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-89327200-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2072863.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 15-89327201-C-T is Pathogenic according to our data. Variant chr15-89327201-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89327201-C-T is described in Lovd as [Pathogenic]. Variant chr15-89327201-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1399G>A	p.Ala467Thr	missense_variant	7/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*671G>A		3_prime_UTR_variant	7/23
POLG	NM_001126131.2	c.1399G>A	p.Ala467Thr	missense_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1399G>A	p.Ala467Thr	missense_variant	7/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000513 AC: 129 AN: 251484 Hom.: 0 AF XY: 0.000522 AC XY: 71 AN XY: 135918

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000578

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: 0.00102

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00105 AC: 1537 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00103 AC XY: 748 AN XY: 727244

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000617 AC XY: 46 AN XY: 74514

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.000627

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00124

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:48Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 17, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 03, 2022	DNA sequence analysis of the POLG gene demonstrated a sequence change, c.1399G>A, in exon 7 that results in an amino acid change, p.Ala467Thr. The p.Ala467Thr change affects a highly conserved amino acid residue located in a domain of the POLG protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala467Thr substitution. This pathogenic sequence change has previously been described as the most common POLG variant associated with autosomal recessive Alpers-Huttenlocher syndrome (PMID: 20301791). This sequence change has been associated with reduced enzyme activity (PMID: 20301791). This sequence change has been described in the gnomAD database with a frequency of 0.05% in the overall population (dbSNP rs113994095). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 07, 2022	PP3, PM2, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Sep 07, 2022	The frequency of this variant in the general population is consistent with pathogenicity ((Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with different autosomal recessive POLG-related disorders. Assessment of experimental evidence suggests this variant results in abnormal protein function. In an in vitro study, this variant abrogated polymerase activity, processivity, and exonuclease activity (PMID: 27987238). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	POLG: PM3:Very Strong, PP1:Strong, PS3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	Identified in individuals with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in patients with Alpers syndrome, sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (vanGoethem et al., 2001); Published functional studies demonstrate a damaging effect (Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22616202, 16368709, 11431686, 20837861, 21235791, 21686371, 22189570, 21515089, 22342071, 23448099, 22995991, 15917273, 21993618, 23212759, 18500570, 23430834, 24272679, 23783014, 20576279, 20691285, 20818383, 22931735, 22006280, 21647632, 25286830, 20138553, 21880868, 16024923, 26104464, 26735972, 27987238, 15122711, 15824347, 18783964, 19501198, 19766516, 28771251, 19813183, 19538466, 29588995, 18546343, 24725338, 29655203, 30167885, 30423451, 30369941, 27422324, 31980526, 31589614, 33473333) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	The POLG c.1399G>A; p.Ala467Thr variant (rs113994095) is reported in association with recessive forms of disease. This variant is one of the most common pathogenic variants in POLG (Cohen 2018) and is reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with POLG-related disorders (Horvath 2006, Luoma 2005, Tzoulis 2006, Van Goethem 2001). This variant is also reported as pathogenic in ClinVar (Variation ID: 13496) and is found in the general population with an overall allele frequency of 0.05% (143/282,888 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.884). Functional studies of the variant protein suggest it has reduced affinity for DNA and has significantly decreased polymerase activity compared to wildtype POLG (Chan 2005, Luoma 2006). Based on available information, this variant is considered to be pathogenic. References: Chan SS et al. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005 Sep 9;280(36):31341-6. PMID: 16024923. Cohen BH et al. POLG-Related Disorders. GeneReviews. 2018. (https://www.ncbi.nlm.nih.gov/books/NBK26471/). PMID: 20301791. Horvath R et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. PMID: 16621917. Luoma PT et al. Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet. 2005 Jul 15;14(14):1907-20. PMID: 15917273. Tzoulis C et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain. 2006 Jul;129(Pt 7):1685-92. PMID: 16638794. Van Goethem G et al. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001 Jul;28(3):211-2. PMID: 11431686. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2017	- -

Progressive sclerosing poliodystrophy Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 03, 2018	This is the most common pathogenic variant described in cases of Alpers-Huttenlocher syndrome (Mitochondrial DNA depletion syndrome 4A (Alpers type), MIM 203700), we have sparse records on the patient's phenotype (long deceased), but it seems a very reasonable clinical fit, albeit perhaps somewhat late onset (age 11). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 22, 2020	0102 - Loss of function is a known mechanism of disease in this gene and is associated with POLG-related mitochondrial disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene predominantly cause recessive disease however, progressive external ophthalmoplegia can also be dominantly inherited (OMIM). (I) 0112 - Autosomal dominant progressive external ophthalmoplegia associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 143 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the linker region (PMID: 16024923). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is one of the most reported variants predominantly in homozygous and compound heterozygous individuals with mitochondrial DNA depletion syndrome 4A (Alpers type) (ClinVar, PMID: 20301791). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 467 of the POLG protein (p.Ala467Thr). This variant is present in population databases (rs113994095, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders, Alpers-Huttenlocher syndrome, autosomal recessive progressive external ophthalmoplegia, sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO), and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and myopathy (PMID: 11431686, 15122711, 15917273, 20691285, 25286830, 26735972). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13496). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 15917273, 16024923). For these reasons, this variant has been classified as Pathogenic. -
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.1399G>A (NP_002684.1:p.Ala467Thr) [GRCH38: NC_000015.10:g.89327201C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS3:Well established functional studies show a deleterious effect on POLG. PS4:Prevalence of variant in affecteds statistically increased over controls. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2014	The Ala467Thr variant in POLG has been reported in >20 individuals with mitochondrial disease in both the homozygous and compound heterozygous states, with symptoms ranging from progressive external ophthalmoplegia to intractable epilepsy to Alpers syndrome (van Goethem 2001, van Goethem 2004, Ferrari 2005, Winterthun 2005, Lax 2012, Scalais 2012, Uusimaa 2012). This variant has also been identified in 0.14% (12/8598) of European American chromosomes and 0.09% (4/4400) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/. In vitro functional studies have shown that the Ala467Thr variant leads to loss of wild-type activity and binding affinity (Chan 2005, Luoma 2005). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace alanine with threonine at codon 467 of the POLG protein (p.Ala467Thr). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in a helix within the linker region. There is a small physicochemical difference between alanine and threonine. The variant is present in a large population cohort at a frequency of 0.051%] (rs113994095, 143/282,888 alleles, 0 homozygotes in gnomAD v2.1). The variant is the most commonly reported POLG variant. It has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in various POLG-related disorders, and segregates with disease in multiple families (PMID: 11431686, 15122711, 15917273, 21880868 - PM3_VeryStrong, PP1_Moderate). In vitro assays show reduced enzyme activity and DNA binding for the variant (PMID: 15917273, 16024923 - PS3_Supporting). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Moderate, PS3_Supporting, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2022	The POLG gene encodes the alpha subunit of polymerase gamma, a mitochondrial DNA polymerase. Pathogenic variants in POLG have been assocaited with Mitochondrial DNA depletion syndrome types 4A and 4B as well as autosomal dominant and recessive forms of Progressive external ophthalmoplegia (OMIM 174763). Variant Interpretation The POLG c.1399G>A missense variant is classified as PATHOGENIC (PS4, PM3, PS3, PP3) The POLG c.1399G>A missense variant is a single nucleotide change in exon 7 of the POLG gene, which is predicted to change the amino acid alanine at position 467 in the protein to threonine. This recurrent variant has been reported in both homozgous and compound heterozygous state in multiple patients with autosomal recessive progressive external ophthalmoplegia 1 (PMID: 11431686, 15824347) (PS4, PM3). Functional studies have demonstrated a significant reduction (96%) in gamma DNA polymerase enzyme activity in mutant cells compared with wild-type (PMID: 16024923) (PS3). This variant has been reported in dbSNP (rs113994095) and has been reported in population databases (gnomAD allele frequency = 0.048%, 143 het and 0 hom in 282888 sequenced alleles). this variant has been reported in ClinVar as pathogenic by multiple diagnostic laboratories (Variation ID: 13496). It has been reported as damaging for Progressive external ophthalmoplegia in the HGMD disease database (CM30938). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

POLG-related disorder Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The POLG c.1399G>A (p.A467T) variant is the most common POLG variant associated with autosomal recessive Alpers-Huttenlocher syndrome (characterized by seizures, loss of mental and movement abilities, and liver disease PMID: 20301791). -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 27, 2018	Submitting this as a novel interpretation as this patient's phenotype does not fit any of the POLG-associated conditions listed in OMIM. This is a different observation than SCV000837701.1 where we observed this variant in a compound heterozygous state with another POLG variant and the patient fit the POLG-related conditions listed in OMIM. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 23, 2024	The POLG c.1399G>A variant is predicted to result in the amino acid substitution p.Ala467Thr. This variant has commonly been reported to be causative for autosomal recessive POLG-related disorders (Rajakulendran et al. 2016. PubMed ID: 26735972; Saneto et al. 2010. PubMed ID: 20138553; Van Goethem et al. 2001. PubMed ID: 11431686; Ferrari et al. 2005. PubMed ID: 15689359; Chan et al. 2005. PubMed ID: 16024923). In vitro functional studies have shown that this variant leads to loss of activity and binding affinity (Chan et al. 2005. PubMed ID: 16024923; Luoma et al. 2005. PubMed ID: 15917273; Kasahara et al. 2017. PubMed ID: 27987238). This variant is reported in 0.098% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 04, 2022	ACMG classification criteria: PS4 strong, PM3 very strong, PP1 strong, PP3 supporting, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2018	- -

POLG-Related Spectrum Disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 06, 2022	Variant summary: POLG c.1399G>A (p.Ala467Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 251484 control chromosomes (gnomAD). c.1399G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with POLG-Related Spectrum Disorders (e.g. Van Goethem_2003, Luoma_2005, Winterthun_2005, Kollberg_2006). These data indicate that the variant is very likely to be associated with disease. Functional analysis using purified recombinant protein showed the variant had reduced binding affinity to DNA and reduced DNA synthesis activity (14% and 18% of controls, respectively. Luoma_2005). Twenty-five ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Dec 16, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID 19578034 etc.] -

Mitochondrial disease Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	Apr 07, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2018

The p.A467T pathogenic mutation (also known as c.1399G>A), located in coding exon 6 of the POLG gene, results from a G to A substitution at nucleotide position 1399. The alanine at codon 467 is replaced by threonine, an amino acid with similar properties. This mutation is the most common recessive pathogenic mutation found in POLG and accounts for 31% of all mutant alleles (Tang, et al. S, J. Med. Genet. 2011; 48(10):669-81). This mutation has been identified in both compound heterozygous and homozygous states in many individuals presenting with a wide range of mitochondrial disorders, including but not limited to: Alpers syndrome, juvenile spinocerebellar ataxia-epilepsy syndrome, progressive external ophthalmoplegia, and other POLG-related disorders including ataxia, neuropathy, epilepsy, hepatopathy, and myopathy (Chan SS et al. J. Biol. Chem. 2005; 280(36):31341-6; Tang SJ et al. J. Med. Genet. 2011;48(10):669-81; Van Goethem Get al. Nat. Genet. 2001;28(3):211-2; Van Goethem G et al. Neuromuscul. Disord. 2003;13(2):133-42; Luoma PT et al. Hum. Mol. Genet. 2005;14(14):1907-20). In addition, this mutation is located in the polymerase domain (also known as the linker region) of POLG, has been found to result in 4-20% of wild-type DNA polymerase activity and fails to interact with the catalytic accessory subunit resulting in compromised catalytic activity (Chan SS et al. J. Biol. Chem. 2005; 280(36):31341-6). Of note, in one family, this mutation caused a mild dominant manifestation of late onset ptosis which required operative correction in three affected individuals (Luoma PT et al. Hum. Mol. Genet. 2005; 14(14):1907-20). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2020

- -

Mitochondrial DNA depletion syndrome 4b Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 07, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3. -

Spinocerebellar ataxia with epilepsy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 11, 2011

- -

Progressive sclerosing poliodystrophy;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Aug 23, 2021

PS3, PS4, PM1, PM3, PP3 -

Tip-toe gait Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Nov 08, 2018

- -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Jul 21, 2020

This variant has been previously reported as a homozygous and a compound heterozygous change in multiple patients and reported to segregate in several families affected by autosomal recessive POLG-related disorders including Alpers-Huttenlocher syndrome (AHS), progressive ataxic neuropathy, Parieto-occipital lobe epilepsy and Mitochondrial neurogastrointestinal encephalomyopathy-like syndrome (PMID: 11431686, 26735972, 15122711, 25286830, 20691285, 15917273). This is the most common AHS-causing variant in the POLG gene. Functional characterization indicates that the p.Ala467Thr variant, which is located near the exonuclease domain in the early linker region of the protein, severely reduces DNA polymerase gamma activity (down to 4% of wild type activity) by compromising the catalytic efficiency of the POLG protein (PMID: 16024923, 15917273). In addition, p.Ala467Thr fails to associate with the POLG2 accessory subunit, which leads to stalling at the replication fork and depletion of mtDNA over time (PMID: 16024923, 27987238, 16368709). The p.Ala467Thr variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.051% (143/282888) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.1399G>A (p.Ala467Thr) variant on protein function. Based on the available evidence, the c.1399G>A (p.Ala467Thr) variant is classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.15

D

BayesDel_noAF

Pathogenic

0.41

Cadd

Pathogenic

27

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

D

M_CAP

Uncertain

0.22

D

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

0.78

D

MutationAssessor

Benign

1.9

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

T

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.055

T;T

Polyphen

1.0

D;D

Vest4

0.92

MVP

0.98

MPC

0.65

ClinPred

0.16

T

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.77

gMVP

0.68

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: rs113994095; hg19: chr15-89870432;