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.
ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(40)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
40
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002693.3(POLG):c.2542G>A (p.Gly848Ser)
Variation ID: 13502 Accession: VCV000013502.82
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q26.1 15: 89321792 (GRCh38) [ NCBI UCSC ] 15: 89865023 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Nov 24, 2024 Jul 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002693.3:c.2542G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Gly848Ser missense NM_001126131.2:c.2542G>A NP_001119603.1:p.Gly848Ser missense NC_000015.10:g.89321792C>T NC_000015.9:g.89865023C>T NG_008218.2:g.18004G>A LRG_765:g.18004G>A LRG_765t1:c.2542G>A LRG_765p1:p.Gly848Ser P54098:p.Gly848Ser - Protein change
- G848S
- Other names
-
p.G848S:GGC>AGC
NM_001126131.1(POLG):c.2542G>A(p.Gly848Ser)
NM_002693.2(POLG):c.2542G>A(p.Gly848Ser)
- Canonical SPDI
- NC_000015.10:89321791:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00015
Exome Aggregation Consortium (ExAC) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00028
1000 Genomes Project 30x 0.00031
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| POLG | - | - |
GRCh38 GRCh37 |
1883 | 3025 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Mar 24, 2009 | RCV000014449.27 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 24, 2009 | RCV000014450.32 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000014451.48 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 24, 2009 | RCV000014452.32 | |
| Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Jul 22, 2024 | RCV000188580.55 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2022 | RCV000363602.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 17, 2021 | RCV000678386.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 12, 2022 | RCV000515163.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2021 | RCV001027839.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2022 | RCV002054437.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2018 | RCV001847601.10 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 2, 2022 | RCV002272018.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 27, 2017 | RCV002313707.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV003230362.8 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Nov 10, 2023 | RCV003231103.12 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002107104.2
First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Mar 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Progressive sclerosing poliodystrophy Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Mitochondrial DNA depletion syndrome 1 Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Mitochondrial DNA depletion syndrome 4b
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611298.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010403.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-related disorder
Affected status: unknown
Allele origin:
maternal
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV004102724.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205836.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 12, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4A (Alpers type)
Affected status: unknown
Allele origin:
germline
|
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236513.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
|
|
|
Pathogenic
(Jan 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511422.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803530.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Comment:
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: … (more)
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). (less)
|
|
|
Pathogenic
(Aug 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331837.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(Oct 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000887116.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000394274.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen … (more)
The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen et al. 2014). Haplotype analysis suggests it is most likely derived from a single ancient ancestor of European origin (Hakonen et al. 2007). The p.Gly848Ser variant has been reported in association with varied autosomal recessive phenotypes, but not in association with autosomal dominant POLG-related disorders. Across a selection of the available literature, the p.Gly848Ser variant is reported in a homozygous state in one individual with seizures who died suddenly at age five, and in a compound heterozygous state in three individuals with autosomal recessive progressive external ophthalmoplegia, two individuals with sensory ataxia neuropathy dysarthria and ophthalmoplegia, two individuals with Alpers syndrome and one individual with intractable epilepsy (Lamantea et al. 2002; Weiss et al. 2010; Milone et al. 2011; Gáti et al. 2011; Tang et al. 2011; Lax et al. 2012; Scalais et al. 2012; Uusimaa et al. 2013; Simon et al. 2014). It was also identified in one individual with progressive external ophthalmoplegia in a double heterozygous state along with a missense variant in the C10orf2 gene (Van Goethem et al. 2003). The p.Gly848Ser variant has also been identified in three unaffected heterozygous individuals (Lamantea et al. 2002). Segregation analysis in multiple families showed the p.Gly848Ser variant segregated with POLG-related disorders. The variant is absent from 200 control individuals and from 180 control chromosomes (Lamantea et al. 2002; Van Goethem et al. 2003; Tang et al. 2011) and is reported at a frequency of 0.00034 in the European (non-Finnish) population of the Genome Aggregation Database. 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. Based on the collective evidence, the p.Gly848Ser variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447477.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypotonia (present) , Global developmental delay (present) , Status epilepticus (present) , Epilepsia partialis continua (present) , Anemia (present) , Central diabetes insipidus (present) , … (more)
Hypotonia (present) , Global developmental delay (present) , Status epilepticus (present) , Epilepsia partialis continua (present) , Anemia (present) , Central diabetes insipidus (present) , Encephalopathy (present) (less)
Sex: female
|
|
|
Pathogenic
(Apr 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000614716.3
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jul 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Mitochondrial DNA depletion syndrome 4b Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984826.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
paternal
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001554491.2
First in ClinVar: Apr 13, 2021 Last updated: Mar 02, 2022 |
|
|
|
Pathogenic
(Nov 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105571.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Pathogenic
(Jan 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Mitochondrial DNA depletion syndrome 4b Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002496144.1
First in ClinVar: Apr 12, 2022 Last updated: Apr 12, 2022 |
Comment:
ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Sep 07, 2017)
|
criteria provided, single submitter
Method: provider interpretation, clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: unknown
Allele origin:
paternal
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804455.2
First in ClinVar: Sep 07, 2018 Last updated: Dec 11, 2022 |
Comment:
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 … (more)
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). (less)
Observation 1:
Clinical Features:
Autistic disorder of childhood onset (present)
Age: 0-9 years
Sex: female
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-06-09
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Autistic disorder of childhood onset (present)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-06-09
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(Apr 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761805.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Feb 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000242202.12
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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) (less)
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Pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mitochondrial DNA depletion syndrome 4b Progressive sclerosing poliodystrophy Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190459.2
First in ClinVar: Mar 26, 2020 Last updated: May 06, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929297.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019466.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
maternal
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV004543837.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Sex: female
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543865.10
First in ClinVar: Apr 16, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Jan 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000848835.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892141.28
First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024 |
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Number of individuals with the variant: 9
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Pathogenic
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005400015.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Jul 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414297.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PM3_strong, PS3, PS4_moderate
Number of individuals with the variant: 2
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Pathogenic
(Mar 24, 2009)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034699.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2015 |
Comment on evidence:
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) … (more)
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. (less)
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Pathogenic
(Mar 24, 2009)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034701.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2015 |
Comment on evidence:
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) … (more)
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. (less)
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Pathogenic
(Mar 24, 2009)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, DIGENIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034700.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2015 |
Comment on evidence:
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) … (more)
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. (less)
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Pathogenic
(Mar 24, 2009)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034702.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2015 |
Comment on evidence:
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) … (more)
In a patient with autosomal recessive PEO (PEOB1; 258450), Lamantea et al. (2002) identified compound heterozygosity for 2 mutations in the POLG gene: gly848-to-ser (G848S) and thr251-to-ile (T251I; 174763.0007). In a patient with PEO, Van Goethem et al. (2003) identified a heterozygous G848S mutation in the POLG gene and a heterozygous arg334-to-gln mutation in the C10ORF2 gene (R334Q; 606075.0008), indicating a digenic mode of inheritance. In 4 children with mitochondrial DNA depletion syndrome-4A (MTDPS4A; 203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and W748S (174763.0013). All patients died in childhood. Davidzon et al. (2005) noted that the G848S mutation occurs within the polymerase motif C of the enzyme. Nguyen et al. (2005) reported 2 unrelated patients with mtDNA depletion syndrome-4A, manifest as Alpers syndrome. One was compound heterozygous for G848S and A467T (174763.0002), and the other was compound heterozygous for G848S and W748S. Hakonen et al. (2007) presented evidence that the G848S disease chromosome originated from a common founder, possibly of European origin. In an infant with mtDNA depletion syndrome-4B (MTDPS4B; 613662), manifest as severe hypotonia and gastrointestinal dysmotility (MNGIE), Giordano et al. (2009) identified compound heterozygosity for 2 mutations in the POLG gene: G848S and a 697C-T transition, resulting in an arg227-to-trp (R227W; 174763.0021) substitution. Other features included hearing loss and clubfoot. Brain MRI showed enlarged ventricles, but leukoencephalopathy was not noted. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was mainly confined to the external layer of the muscularis propria. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955119.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965694.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Mar 19, 2024)
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no assertion criteria provided
Method: clinical testing
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POLG-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120250.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807715.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740770.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Mitochondrial disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040910.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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POLG-related disorder
Affected status: yes, unknown
Allele origin:
unknown,
paternal
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GenomeConnect, ClinGen
Accession: SCV000607021.3
First in ClinVar: Oct 16, 2017 Last updated: Jun 10, 2023 |
Comment:
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 … (more)
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. (less)
Observation 1:
Clinical Features:
Abnormal lens morphology (present) , Depression (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Decreased pulmonary function … (more)
Abnormal lens morphology (present) , Depression (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Decreased pulmonary function (present) , Respiratory insufficiency (present) , Abnormality of the upper respiratory tract (present) , Abnormal esophagus morphology (present) (less)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-10-26
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Failure to thrive (present) , Abnormal facial shape (present) , Generalized hypotonia (present) , Abnormality of the somatic nervous system (present) , Abnormality of the … (more)
Failure to thrive (present) , Abnormal facial shape (present) , Generalized hypotonia (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) , Cardiomyopathy (present) , Feeding difficulties (present) , Abnormality of the liver (present) , Gastrointestinal dysmotility (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-10-31
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
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).
Comment:
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.
Comment:
The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen et al. 2014). Haplotype analysis suggests it is most likely derived from a single ancient ancestor of European origin (Hakonen et al. 2007). The p.Gly848Ser variant has been reported in association with varied autosomal recessive phenotypes, but not in association with autosomal dominant POLG-related disorders. Across a selection of the available literature, the p.Gly848Ser variant is reported in a homozygous state in one individual with seizures who died suddenly at age five, and in a compound heterozygous state in three individuals with autosomal recessive progressive external ophthalmoplegia, two individuals with sensory ataxia neuropathy dysarthria and ophthalmoplegia, two individuals with Alpers syndrome and one individual with intractable epilepsy (Lamantea et al. 2002; Weiss et al. 2010; Milone et al. 2011; Gáti et al. 2011; Tang et al. 2011; Lax et al. 2012; Scalais et al. 2012; Uusimaa et al. 2013; Simon et al. 2014). It was also identified in one individual with progressive external ophthalmoplegia in a double heterozygous state along with a missense variant in the C10orf2 gene (Van Goethem et al. 2003). The p.Gly848Ser variant has also been identified in three unaffected heterozygous individuals (Lamantea et al. 2002). Segregation analysis in multiple families showed the p.Gly848Ser variant segregated with POLG-related disorders. The variant is absent from 200 control individuals and from 180 control chromosomes (Lamantea et al. 2002; Van Goethem et al. 2003; Tang et al. 2011) and is reported at a frequency of 0.00034 in the European (non-Finnish) population of the Genome Aggregation Database. 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. Based on the collective evidence, the p.Gly848Ser variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
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.
Comment:
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.
Comment:
ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1
Comment:
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).
Comment:
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).
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Comment:
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
Comment:
PP3, PM3_strong, PS3, PS4_moderate
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
The POLG c.2542G>A (p.Gly848Ser) missense variant is well-documented as one of the three most common pathogenic disease-causing variants found in patients with POLG-related disorders (Cohen et al. 2014). Haplotype analysis suggests it is most likely derived from a single ancient ancestor of European origin (Hakonen et al. 2007). The p.Gly848Ser variant has been reported in association with varied autosomal recessive phenotypes, but not in association with autosomal dominant POLG-related disorders. Across a selection of the available literature, the p.Gly848Ser variant is reported in a homozygous state in one individual with seizures who died suddenly at age five, and in a compound heterozygous state in three individuals with autosomal recessive progressive external ophthalmoplegia, two individuals with sensory ataxia neuropathy dysarthria and ophthalmoplegia, two individuals with Alpers syndrome and one individual with intractable epilepsy (Lamantea et al. 2002; Weiss et al. 2010; Milone et al. 2011; Gáti et al. 2011; Tang et al. 2011; Lax et al. 2012; Scalais et al. 2012; Uusimaa et al. 2013; Simon et al. 2014). It was also identified in one individual with progressive external ophthalmoplegia in a double heterozygous state along with a missense variant in the C10orf2 gene (Van Goethem et al. 2003). The p.Gly848Ser variant has also been identified in three unaffected heterozygous individuals (Lamantea et al. 2002). Segregation analysis in multiple families showed the p.Gly848Ser variant segregated with POLG-related disorders. The variant is absent from 200 control individuals and from 180 control chromosomes (Lamantea et al. 2002; Van Goethem et al. 2003; Tang et al. 2011) and is reported at a frequency of 0.00034 in the European (non-Finnish) population of the Genome Aggregation Database. 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. Based on the collective evidence, the p.Gly848Ser variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
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.
Comment:
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.
Comment:
ACMG categories: PS3,PM1,PM2,PP3,PP5,BP1
Comment:
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).
Comment:
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).
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Comment:
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
Comment:
PP3, PM3_strong, PS3, PS4_moderate
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| POLG-Related Disorders. | Adam MP | - | 2024 | PMID: 20301791 |
| Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network. | Denommé-Pichon AS | European journal of human genetics : EJHG | 2022 | PMID: 34782754 |
| Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes. | Bychkov IO | Mitochondrion | 2021 | PMID: 33486010 |
| POLG-related disorders and their neurological manifestations. | Rahman S | Nature reviews. Neurology | 2019 | PMID: 30451971 |
| Pathogenicity in POLG syndromes: DNA polymerase gamma pathogenicity prediction server and database. | Nurminen A | BBA clinical | 2017 | PMID: 28480171 |
| The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. | Hikmat O | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471437 |
| Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson's disease. | Gui YX | Parkinsonism & related disorders | 2015 | PMID: 25585994 |
| Abnormalities in glycogen metabolism in a patient with alpers' syndrome presenting with hypoglycemia. | Simon M | JIMD reports | 2014 | PMID: 24272679 |
| Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features. | Uusimaa J | Epilepsia | 2013 | PMID: 23448099 |
| Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy. | Scalais E | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2012 | PMID: 22342071 |
| Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. | Lax NZ | Brain : a journal of neurology | 2012 | PMID: 22189570 |
| Sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO). Two case reports. | Gáti I | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2011 | PMID: 22616202 |
| Bowel obstruction in patients with Alpers-Huttenlocher syndrome. | Spiegler J | Neuropediatrics | 2011 | PMID: 22006280 |
| Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. | Tang S | Journal of medical genetics | 2011 | PMID: 21880868 |
| Novel POLG splice site mutation and optic atrophy. | Milone M | Archives of neurology | 2011 | PMID: 21670405 |
| Sequence-specific stalling of DNA polymerase γ and the effects of mutations causing progressive ophthalmoplegia. | Atanassova N | Human molecular genetics | 2011 | PMID: 21228000 |
| High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
| Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) in late life due to compound heterozygous POLG mutations. | Weiss MD | Muscle & nerve | 2010 | PMID: 20513108 |
| Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. | Kasiviswanathan R | The Journal of biological chemistry | 2009 | PMID: 19478085 |
| Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to POLG1 mutations. | Giordano C | Neurology | 2009 | PMID: 19307547 |
| Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. | Taanman JW | Human mutation | 2009 | PMID: 18828154 |
| Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: a cautionary note. | de Vries MC | Journal of inherited metabolic disease | 2008 | PMID: 18500570 |
| Mitochondrial DNA defects in Saccharomyces cerevisiae caused by functional interactions between DNA polymerase gamma mutations associated with disease in human. | Baruffini E | Biochimica et biophysica acta | 2007 | PMID: 17980715 |
| Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. | Hakonen AH | European journal of human genetics : EJHG | 2007 | PMID: 17426723 |
| POLG mutations in Alpers syndrome. | Nguyen KV | Neurology | 2005 | PMID: 16177225 |
| POLG mutations and Alpers syndrome. | Davidzon G | Annals of neurology | 2005 | PMID: 15929042 |
| Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. | Ferrari G | Brain : a journal of neurology | 2005 | PMID: 15689359 |
| Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene. | Lamantea E | Annals of neurology | 2004 | PMID: 15349879 |
| Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. | Van Goethem G | Human mutation | 2003 | PMID: 12872260 |
| Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. | Lamantea E | Annals of neurology | 2002 | PMID: 12210792 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs113994098 ...
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Record last updated Nov 25, 2024
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