Submissions for variant NM_002693.3(POLG):c.1399G>A (p.Ala467Thr)

gnomAD frequency: 0.00068  dbSNP: rs113994095

Total submissions: 51

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000184011	SCV000236534	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2013-12-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000188658	SCV000242281	pathogenic	not provided	2019-11-25	criteria provided, single submitter	clinical testing	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014440	SCV000245651	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2014-04-24	criteria provided, single submitter	clinical testing	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).
Eurofins Ntd Llc (ga)	RCV000188658	SCV000331833	pathogenic	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000347876	SCV000394291	pathogenic	POLG-Related Spectrum Disorders	2016-06-14	criteria provided, single submitter	clinical testing	The c.1399G>A (p.Ala467Thr) variant is well described in the literature as one of the most common mutations associated with POLG-related disorders, particularly Alpert-Huttenlocher syndrome (Chan et al. 2005; Cohen et al. 2014; Rajakulendran et al. 2016). Across a selection of the literature, the p.Ala467Thr variant has been identified in at least 52 patients including 15 in a homozygous state and 37 in a compound heterozygous state (van Goethem et al. 2001; Tzoulis et al. 2006; Tang et al. 2011; Uusimaa et al. 2013; Rajakulendran et al. 2016). In addition the variant has been found in 154 out of 498 patient alleles (31%) (Tang et al. 2011). The p.Ala467Thr variant was found in three out of 229 controls in one study and is reported at a frequency of 0.001400 in the European American population of the Exome Sequencing Project. Functional studies have demonstrated that the p.Ala467Thr variant results in a drastically reduced polymerase gamma activity to 4 - 18% of the wild type, reduced DNA binding capability to 14% of the control value, and a reduction in a processivity due to an impaired interaction with the accessory subunit of the enzyme which then slows the rate of DNA synthesis (Chan et al. 2005; Luoma et al. 2005). Based on the collective evidence the p.Ala467Thr variant is classified as pathogenic for POLG-Related Disorders.
CeGaT Center for Human Genetics Tuebingen	RCV000188658	SCV000493450	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	POLG: PM3:Very Strong, PP1:Strong, PS3, PM2
Fulgent Genetics, Fulgent Genetics	RCV000515354	SCV000611297	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2021-12-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000188658	SCV000614701	pathogenic	not provided	2022-09-07	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014443	SCV000630094	pathogenic	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000188658	SCV000802092	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing	PP3, PM2, PM3, PS3, PS4_moderate
Undiagnosed Diseases Network, NIH	RCV000014443	SCV000837702	pathogenic	Progressive sclerosing poliodystrophy	2018-01-03	criteria provided, single submitter	clinical testing	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).
Ambry Genetics	RCV002316195	SCV000851036	pathogenic	Inborn genetic diseases	2021-10-22	criteria provided, single submitter	clinical testing	The c.1399G>A (p.A467T) alteration is located in exon 7 (coding exon 6) of the POLG gene. This alteration results from a G to A substitution at nucleotide position 1399, causing the alanine (A) at amino acid position 467 to be replaced by a threonine (T). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, the association of this alteration with autosomal dominant progressive external ophthalmoplegia is unlikely. Based on data from gnomAD, the A allele has an overall frequency of 0.05% (143/282888) total alleles studied. The highest observed frequency was 0.1% (127/129190) of European (non-Finnish) alleles. This mutation is the most common recessive pathogenic mutation found in POLG and accounts for 31% of all mutant alleles (Tang, 2011). 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, 2005; Tang, 2011; Van Goethem, 2001; Van Goethem, 2004; Luoma, 2005; Janssen, 2016; Rajakulendran, 2016). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies demonstrate that the p.A467T mutation results in 4-20% of wild-type DNA polymerase activity and fails to interact with the catalytic accessory subunit resulting in compromised catalytic activity (Chan, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Undiagnosed Diseases Network, NIH	RCV001095683	SCV000863407	pathogenic	POLG-related disorder	2018-06-27	criteria provided, single submitter	clinical testing	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000014443	SCV000886901	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000014441	SCV001150219	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2018-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004604	SCV001163774	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095683	SCV001251460	pathogenic	POLG-related disorder		criteria provided, single submitter	research	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198082	SCV001368867	pathogenic	Mitochondrial DNA depletion syndrome 4b	2019-05-07	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188658	SCV001447214	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000184011	SCV001522833	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1	2020-03-26	criteria provided, single submitter	clinical testing	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.]
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000014443	SCV001554492	pathogenic	Progressive sclerosing poliodystrophy		criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001376079	SCV001573093	pathogenic	Tip-toe gait	2018-11-08	criteria provided, single submitter	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001731286	SCV001984827	pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2020-07-21	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000188658	SCV002019460	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001813983	SCV002061523	pathogenic	Progressive sclerosing poliodystrophy; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2021-08-23	criteria provided, single submitter	clinical testing	PS3, PS4, PM1, PM3, PP3
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847600	SCV002105549	pathogenic	Hereditary spastic paraplegia	2020-05-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000188658	SCV002502115	pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000014440	SCV002503861	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2023-03-30	criteria provided, single submitter	clinical testing	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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273931	SCV002559145	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000014443	SCV002581865	pathogenic	Progressive sclerosing poliodystrophy	2022-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000347876	SCV002819290	pathogenic	POLG-Related Spectrum Disorders	2022-12-06	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000014441	SCV003806775	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2022-08-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM3 very strong, PP1 strong, PP3 supporting, PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014443	SCV003921773	pathogenic	Progressive sclerosing poliodystrophy	2020-07-22	criteria provided, single submitter	clinical testing	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
Genetics and Molecular Pathology, SA Pathology	RCV000014440	SCV004175638	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-12-13	criteria provided, single submitter	clinical testing	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).
Baylor Genetics	RCV000014443	SCV004205837	pathogenic	Progressive sclerosing poliodystrophy	2024-03-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000188658	SCV004564949	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing	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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000188658	SCV005197250	pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing
OMIM	RCV000014440	SCV000034690	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2011-02-11	no assertion criteria provided	literature only
OMIM	RCV000014441	SCV000034691	pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2011-02-11	no assertion criteria provided	literature only
OMIM	RCV000014442	SCV000034692	pathogenic	Spinocerebellar ataxia with epilepsy	2011-02-11	no assertion criteria provided	literature only
OMIM	RCV000014443	SCV000034693	pathogenic	Progressive sclerosing poliodystrophy	2011-02-11	no assertion criteria provided	literature only
GeneReviews	RCV000508942	SCV000040905	not provided	Mitochondrial disease		no assertion provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508942	SCV000575914	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001095683	SCV000840346	not provided	POLG-related disorder		no assertion provided	phenotyping only	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000188658	SCV001743413	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000188658	SCV001797643	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000188658	SCV001807996	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000188658	SCV001955733	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000188658	SCV001968652	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000188658	SCV003839906	pathogenic	not provided	2022-09-03	no assertion criteria provided	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV001095683	SCV004116148	pathogenic	POLG-related disorder	2024-05-09	no assertion criteria provided	clinical testing	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.