rs113994098
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The ENST00000268124.11(POLG):c.2542G>A(p.Gly848Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G848G) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 0 hom. )
Consequence
POLG
ENST00000268124.11 missense
ENST00000268124.11 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 7.50
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000268124.11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
Variant 15-89321792-C-T is Pathogenic according to our data. Variant chr15-89321792-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89321792-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLG | NM_002693.3 | c.2542G>A | p.Gly848Ser | missense_variant | 16/23 | ENST00000268124.11 | NP_002684.1 | |
| POLGARF | NM_001406557.1 | c.*1814G>A | 3_prime_UTR_variant | 16/23 | NP_001393486.1 | |||
| POLG | NM_001126131.2 | c.2542G>A | p.Gly848Ser | missense_variant | 16/23 | NP_001119603.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLG | ENST00000268124.11 | c.2542G>A | p.Gly848Ser | missense_variant | 16/23 | 1 | NM_002693.3 | ENSP00000268124 | P1 |
Frequencies
GnomAD3 genomes 0.000276 AC: 42AN: 152146Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
42
AN:
152146
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000147 AC: 37AN: 251408Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135894
GnomAD3 exomes
AF:
AC:
37
AN:
251408
Hom.:
AF XY:
AC XY:
18
AN XY:
135894
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000312 AC: 456AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.000301 AC XY: 219AN XY: 727232
GnomAD4 exome
AF:
AC:
456
AN:
1461872
Hom.:
Cov.:
32
AF XY:
AC XY:
219
AN XY:
727232
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000276 AC: 42AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74456
GnomAD4 genome
AF:
AC:
42
AN:
152264
Hom.:
Cov.:
32
AF XY:
AC XY:
24
AN XY:
74456
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
3
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
2
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
19
Asia WGS
AF:
AC:
1
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:38Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:13
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2020 | Accounts for approximately 10% of disease-causing alleles and has been identified in patients with autosomal recessive progressive external ophthalmoplegia (arPEO), Alpers syndrome, Leigh syndrome, SANDO, and other autosomal recessive POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Tang et al., 2011; Human DNA Polymerase Gamma Mutation Database); Published functional studies demonstrate a damaging effect, resulting in significantly impaired polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27538665, 28130605, 31302675, 22616202, 21670405, 22189570, 22342071, 23448099, 12872260, 18500570, 24272679, 20513108, 20818383, 22006280, 25585994, 26692522, 27538604, 12210792, 17980715, 19478085, 27065468, 28139822, 28154168, 21880868, 18991199, 19766516, 28471437, 29655203, 30167885, 30423451, 30552426, 31996268, 33300680) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 02, 2016 | - - |
| 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 | Revvity Omics, Revvity | Feb 15, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 05, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | POLG: PM3:Very Strong, PM2, PP4:Moderate, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 22, 2024 | PP3, PM3_strong, PS3, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 30, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate a loss of >99% of polymerase activity and 5-fold reduction in DNA binding affinity (PMID: 19478085, 21228000). 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. Computational tools predict that this variant is damaging. - |
Progressive sclerosing poliodystrophy Pathogenic:8
| Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Pathogenic, for Mitochondrial DNA depletion syndrome 4A (Alpers type), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Common mutation frequently observed in multiple unrelated patients. (PMID:17426723,21880868). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19478085). PS3 => Well-established functional studies show a deleterious effect (PMID:19478085). - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 24, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 848 of the POLG protein (p.Gly848Ser). This variant is present in population databases (rs113994098, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 12872260, 17426723, 18500570, 21670405, 21880868, 22006280, 22189570, 22342071, 22616202). ClinVar contains an entry for this variant (Variation ID: 13502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 17980715, 19478085). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Jun 12, 2014 | - - |
| 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.2542G>A (NP_002684.1:p.Gly848Ser) [GRCH38: NC_000015.10:g.89321792C>T] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:12210792 ; 16177225 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. 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. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | May 26, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
POLG-related disorder Pathogenic:2Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant reported in multiple GenomeConnect participants by GeneDx. Variant interpreted as Pathogenic and reported, most recently, on 2016-10-31. 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 | Daryl Scott Lab, Baylor College of Medicine | Nov 10, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 19, 2024 | The POLG c.2542G>A variant is predicted to result in the amino acid substitution p.Gly848Ser. This variant has been reported to be causative for a variety of autosomal recessive POLG-associated disorders, such as sensory ataxia neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO), Alpers’ Syndrome, Leigh-like syndrome, intractable epilepsy, and progressive external ophthalmoplegia (PEO) (Gáti et al. 2011. PubMed ID: 22616202; Simon et al. 2014. PubMed ID : 24272679; Uusimaa et al. 2013. PubMed ID : 23448099; Lamantea et al. 2002. PubMed ID: 12210792). The p.Gly848Ser variant protein retained less than 1% of catalytic activity compared to the wild type enzyme (Kasiviswanathan et al. 2009. PubMed ID: 19478085). This variant is reported in 0.0085% of alleles in individuals of African descent in gnomAD. We classify this variant as pathogenic. - |
POLG-Related Spectrum Disorders Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 28, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:19478085; 17980715) - PS3_moderate.The c.2542G>A;p.(Gly848Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13502; PMID: 17426723; PMID: 21880868; PMID: 18500570; PMID: 12872260; PMID: 22616202; PMID: 22006280; PMID: 22342071; PMID: 21670405; PMID: 22189570) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (DNA_pol_A) - PM1. The variant is present at low allele frequencies population databases (rs113994098 – gnomAD 0.001697%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly848Ser) was detected in trans with a pathogenic variant (PMID:19478085) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Sep 07, 2017 | This 7 year old female with autism spectrum disorder was found to carry a paternally inherited missense variant in the POLG gene. Neither she nor her father have any of the features of autosomal dominant POLG-Related Disorder, but it is possible that features have not yet emerged. Metabolic testing has thus far been normal for the patient. The p.G848S variant is a commonly reported pathogenic variant in the POLG gene, representing approximately 10% of disease-causing variants in this gene (Tang et al., 2011). The p.G848S variant was initially identified in a patient with autosomal recessive progressive external ophthalmoplegia (arPEO) and has subsequently been identified in individuals with Alpers syndrome, Leigh syndrome, SANDO, and other POLG-related disorders causing epilepsy, ataxia, neuropathy, hepatopathy, and/or myopathy (Lamantea et al., 2002). This variant alters a highly conserved position in the polymerase domain of POLG, and functional studies indicate that it significantly impairs the enzyme's polymerase activity and DNA binding ability (Kasiviswanathan et al., 2009). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 17, 2021 | The POLG c.2542G>A variant is classified as Pathogenic (PS3, PS4, PP1, PP3) The POLG c.2542G>A variant is a single nucleotide change in exon 16 of the POLG gene, which is predicted to change the amino acid glycine at position 848 in the protein to serine. The variant has been reported in probands with a clinical presentation of progressive external ophthalmoplegia (PS4). Multiple cases reported in literature: 23 entries in ClinVAR ( all P/LP) This variant co-segregates with disease (PP1). 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. Well-established functional studies show a deleterious effect of this variant (PS3). Lamantea et al. (2002) note that the Gly848 residue is highly conserved, and functional studies by Kasiviswanathan et al. (2009) indicate that the p.Gly848Ser variant significantly impairs POLG activity and DNA binding affinity. Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs113994098) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 13502). - |
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:2
| 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 compound heterozygous change in multiple patients with autosomal recessive POLG-related disorders including Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, optic Atrophy, intractable epilepsy and early onset epileptic encephalopathy (PMID: 12210792, 22189570, 23448099, 30552426, 30423451, 29655203). Functional characterization indicates that the p.Gly848Ser variant, which is located in the thumb domain of the protein and affects a conserved glycine residue upstream of motif polA, results in <1% polymerase activity, and in a defect in DNA binding function (PMID: 19478085). In addition, studies in model organisms indicated that the yeast-equivalent of the p.Gly848Ser variant results in high mtDNA instability (PMID: 17980715). The p.Gly848Ser variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (48/282794) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.2542G>A (p.Gly848Ser) variant on protein function. Based on the available evidence, the c.2542G>A (p.Gly848Ser) variant is classified as Pathogenic. - |
| Pathogenic, 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 16 p.Gly848Ser (c.2542G>A): This variant has been reported in the literature in the compound heterozygous or homozygous state in several individuals with autosomal recessive progressive external opthalmoplegia as well as a wide variety of additional POLG-related phenotypes (Lamantea 2002 PMID:12210792, Weiss 2010 PMID:20513108, Milone 2011 PMID:21670405, Tang 2011 PMID:21880868, Scalais 2012 PMID:22342071, Uusimaa 2013 PMID:23448099, Simon 2014 PMID:2014 PMID:24272679). Literature suggests that this variant is one of the most common pathgenic variants in the POLG gene (Hakonen, 2007 PMID:17426723, Tang 2011 PMID:21880868). This variant is present in 0.03% (40/129136) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89865023-C-T). 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, with several labs classifying this variant as pathogenic (Variation ID:13502). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies indicate that this variant leads to decreased enzyme activity and reduced DNA binding affinity (Kasivishwanathan 2009 PMID:19478085). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. - |
Mitochondrial disease Pathogenic:1Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 are usually inherited in a recessive manner, however progressive external ophthalmoplegia may also be dominant when heterozygous variants are located in the highly conserved active site of motif B of the polymerase domain (PMID: 30451971). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 (48 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the DNA polymerase family A domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in greater than 10 unrelated individuals with unrelated individuals with POLG-related mitochondrial disorders (ClinVar, Human DNA POLG Mutation Database, PMID: 21880868, PMID: 28480171, PMID: 23448099, PMID: 15929042, LOVD). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 24, 2009 | - - |
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 | Mar 12, 2022 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2017 | The p.G848S pathogenic mutation (also known as c.2542G>A), located in coding exon 15 of the POLG gene, results from a G to A substitution at nucleotide position 2542. The glycine at codon 848 is replaced by serine, an amino acid with similar properties. This mutation was first described in an individual with progressive external ophthalmoplegia (PEO), cytochrome c oxidase-neg ragged red fibers, and multiple mtDNA deletions in skeletal muscle who was compound heterozygous for another pathogenic POLG alteration (Lamantea E et al. Ann. Neurol., 2002 Aug;52:211-9). This mutation is located in the catalytic polymerase domain and is one of the most common POLG mutations, accounting for approximately 10% of mutant alleles in one large cohort of over 2000 patients with phenotypes suspicious for POLG deficiencies, including autosomal recessive PEO (arPEO), Alpers syndrome, and seizures (Tang S et al. J Med Genet. 2011 Oct;48(10):669-81). Based on the available evidence, p.G848S is classified as a pathogenic mutation. - |
Hereditary spastic paraplegia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 01, 2018 | - - |
Mitochondrial DNA depletion syndrome 4b Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 24, 2009 | - - |
Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;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 | Institute of Human Genetics, University Hospital Muenster | Jan 20, 2022 | ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1 - |
Mitochondrial DNA depletion syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2023 | Variant summary: POLG c.2542G>A (p.Gly848Ser) results in a non-conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251408 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome (0.00015 vs 0.0035), allowing no conclusion about variant significance. c.2542G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Mitochondrial DNA Depletion Syndrome - POLG Related (e.g., Tang_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <1% of normal polymerase activity (e.g., Kasiviswanathan_2009). Multiple ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 24, 2009 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at