Across a selection of available literature, the c.2243G>C (p.Trp748Ser) variant has been identified in a total of 86 patients with POLG-related spectrum disorders including 52 in a homozygous state, 31 in a compound heterozygous state, and three in a heterozygous state (Van Goethem et al. 2004; Hakonen et al. 2005; Tzoulis et al. 2006; Tang et al. 2012). Several of these studies indicate that this variant appears to be in cis with a second missense variant, c.3428A>G (p.Glu1143Gly), which is a relatively common variant suggested by Hankonen et al. (2005) to be a polymorphism. The p.Trp748Ser variant has also been detected in a heterozygous state in unaffected family members (Van Goethem et al. 2004). This p.Trp748Ser variant was reported in two of 976 control chromosomes and at a frequency of 0.00566 in the European (Finnish) population of the Exome Aggregation Consortium. Tang et al. (2012) suggest that the Trp248 residue is evolutionarily conserved. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). Both studies showed a decrease in binding affinity of DNA polymerase to DNA in the presence of the p.Trp748Ser variant, at 1.6-fold and 8-fold reduction, respectively. Based on the collective evidence, the p.Trp748Ser variant is classified as pathogenic for POLG-related spectrum disorders.
ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)
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/Likely pathogenic
40
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_002693.3(POLG):c.2243G>C (p.Trp748Ser)
Variation ID: 13507 Accession: VCV000013507.87
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q26.1 15: 89323426 (GRCh38) [ NCBI UCSC ] 15: 89866657 (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 Oct 20, 2024 Mar 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002693.3:c.2243G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Trp748Ser missense NM_001126131.2:c.2243G>C NP_001119603.1:p.Trp748Ser missense NC_000015.10:g.89323426C>G NC_000015.9:g.89866657C>G NG_008218.2:g.16370G>C LRG_765:g.16370G>C LRG_765t1:c.2243G>C P54098:p.Trp748Ser - Protein change
- W748S
- Other names
-
p.W748S:TGG>TCG
NM_001126131.1(POLG):c.2243G>C(p.Trp748Ser)
NM_002693.2(POLG):c.2243G>C(p.Trp748Ser)
- Canonical SPDI
- NC_000015.10:89323425:C:G
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00084
The Genome Aggregation Database (gnomAD), exomes 0.00097
Trans-Omics for Precision Medicine (TOPMed) 0.00031
The Genome Aggregation Database (gnomAD) 0.00081
- 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 |
1872 | 3014 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2023 | RCV000014459.53 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2007 | RCV000014460.33 | |
| Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000014461.46 | |
| Pathogenic/Likely pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000080023.61 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 12, 2023 | RCV000313739.19 | |
| Pathogenic (2) |
no assertion criteria provided
|
Apr 7, 2017 | RCV000508846.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 25, 2017 | RCV000507757.16 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 28, 2022 | RCV001198081.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247336.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 23, 2023 | RCV002313710.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 2, 2024 | RCV003985719.2 | |
| 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
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000394279.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Across a selection of available literature, the c.2243G>C (p.Trp748Ser) variant has been identified in a total of 86 patients with POLG-related spectrum disorders including 52 … (more)
Across a selection of available literature, the c.2243G>C (p.Trp748Ser) variant has been identified in a total of 86 patients with POLG-related spectrum disorders including 52 in a homozygous state, 31 in a compound heterozygous state, and three in a heterozygous state (Van Goethem et al. 2004; Hakonen et al. 2005; Tzoulis et al. 2006; Tang et al. 2012). Several of these studies indicate that this variant appears to be in cis with a second missense variant, c.3428A>G (p.Glu1143Gly), which is a relatively common variant suggested by Hankonen et al. (2005) to be a polymorphism. The p.Trp748Ser variant has also been detected in a heterozygous state in unaffected family members (Van Goethem et al. 2004). This p.Trp748Ser variant was reported in two of 976 control chromosomes and at a frequency of 0.00566 in the European (Finnish) population of the Exome Aggregation Consortium. Tang et al. (2012) suggest that the Trp248 residue is evolutionarily conserved. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). Both studies showed a decrease in binding affinity of DNA polymerase to DNA in the presence of the p.Trp748Ser variant, at 1.6-fold and 8-fold reduction, respectively. Based on the collective evidence, the p.Trp748Ser variant is classified as pathogenic for POLG-related spectrum disorders. (less)
|
|
|
Pathogenic
(Mar 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604905.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Feb 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331432.4
First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 10
Sex: mixed
|
|
|
Pathogenic
(Aug 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967582.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri … (more)
The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449647.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jun 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4b
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368866.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4.
|
|
|
Pathogenic
(Jan 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242192.10
First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447) (less)
|
|
|
Pathogenic
(Feb 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579578.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PS3_MOD, PM3, PP1, PP3
|
Number of individuals with the variant: 4
Sex: male
|
|
|
Pathogenic
(Jun 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000614711.3
First in ClinVar: Oct 09, 2016 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second … (more)
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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. (less)
|
|
|
Pathogenic
(Apr 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802086.2
First in ClinVar: Aug 04, 2018 Last updated: Jun 03, 2023 |
|
|
|
Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122808.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). 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. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024710.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630126.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
paternal
|
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV004543838.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Sex: female
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205852.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005061102.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Comment:
The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It … (more)
The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It is commonly reported in individuals of Finnish ancestry. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). This variant is reported with the allele frequency (0.09%) in the gnomAD Exomes. It is submitted to ClinVar as uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen – score1.00; Sift – score 0.01; Mutation Taster – score 1.00). The amino acid Trptophan at position 748 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp748Ser in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
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: SCV000887113.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] 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.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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
(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: SCV001448144.1
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
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Affected status: yes
Allele origin:
unknown
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519174.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Likely pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501869.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 4
Secondary finding: no
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518885.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573228.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormality of metabolism/homeostasis (present)
|
|
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Pathogenic
(Aug 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440549.2
First in ClinVar: Oct 31, 2020 Last updated: Oct 01, 2022 |
Comment:
This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4
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Pathogenic
(Jul 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4b
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal,
paternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150218.2
First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
EEG abnormality (present) , Seizure (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Delayed speech and language development (present) , Focal seizures, afebril (present) , Vertical supranuclear gaze palsy (present) , Intellectual disability, mild (present) , Cerebellar ataxia … (more)
Delayed speech and language development (present) , Focal seizures, afebril (present) , Vertical supranuclear gaze palsy (present) , Intellectual disability, mild (present) , Cerebellar ataxia (present) (less)
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Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: curation
|
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803580.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 02, 2023 |
Comment:
This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls … (more)
This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268). (less)
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Pathogenic
(Aug 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812157.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS3,PM3_STR,PS4_MOD,PP3
Clinical Features:
Abnormal CNS myelination (present) , Abnormal pyramidal sign (present) , Gait ataxia (present) , Gait disturbance (present) , Leukodystrophy (present)
Sex: female
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|
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Pathogenic
(Aug 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000848339.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution … (more)
The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2243, causing the tryptophan (W) at amino acid position 748 to be replaced by a serine (S). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.099% (280/282688) total alleles studied. The highest observed frequency was 0.621% (156/25104) of European (Finnish) alleles. The c.2243G>C (p.W748S) alteration accounts for approximately 8% of disease causing alleles in the Finnish population. This alteration has been identified in the homozygous state and in conjunction with another alteration in POLG in multiple individuals with Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO), and other autosomal recessive POLG-related mitochondrial disorders (Bychkov, 2021; Masingue, 2019; Henao, 2016; Hakonen, 2007; Janssen, 2016; Uusimaa, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250415.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Number of individuals with the variant: 10
|
|
|
Pathogenic
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034710.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in … (more)
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. In a follow-up report of the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016). In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. (less)
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Pathogenic
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
SPINOCEREBELLAR ATAXIA WITH EPILEPSY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034711.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in … (more)
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. In a follow-up report of the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016). In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. (less)
|
|
|
Pathogenic
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 4A (ALPERS TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034712.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in … (more)
In 3 Finnish sibs with SANDO (607459) previously reported by Rantamaki et al. (2001), Van Goethem et al. (2004) identified a homozygous 2243G-C transversion in the POLG gene, resulting in a trp748-to-ser (W748S) substitution. The mutated residue lies within a highly conserved block of 6 amino acids that form a beta-sheet in the spacer, or linker, region of the enzyme and is presumed to be involved in primer-template interaction of the DNA polymerase. An unrelated Finnish patient had the same homozygous mutation, and an unrelated British patient was compound heterozygous for W748S and A467T (174763.0002). In addition to the W748S mutation, all 5 patients carried a 3428A-G transition, resulting in a glu1143-to-gly (E1143G) substitution on the same allele. W748S was not identified in 168 Belgian and 70 Finnish controls; E1143G was identified in 11 Belgian and 3 Finnish controls. Van Goethem et al. (2004) concluded that E1143G is a low-frequency polymorphism that forms a common ancestral haplotype; however, they noted that the contribution of E1143G to the phenotype was unclear. In a follow-up report of the family reported by Rantamaki et al. (2001) and Van Goethem et al. (2004), Rantamaki et al. (2007) found that heterozygous W748S carriers showed no clinically manifesting phenotype. Presumably unrelated neurologic signs and symptoms, including dementia, epilepsy, and migraine, were found in several carriers, but clearly defined neurologic diseases did not segregate with the mutation. The only notable finding was a subclinical axonal sensory neuropathy in the majority of carriers. Hakonen et al. (2005) found that the POLG allele with W748S and E1143G in cis is among the most common genetic causes of inherited ataxia in Finland. They identified 27 patients with mitochondrial recessive ataxia syndrome from 15 Finnish families, with a carrier frequency in the general population of 1:125. Since the mutation pair W748S+E1143G has also been described in European patients, they examined the haplotypes of 13 non-Finnish European patients with the W748S mutation. Haplotype analysis demonstrated that all the chromosomes carrying these 2 changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common Northern haplotypes outside the core haplotype could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicated that this form of ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes. Winterthun et al. (2005) identified a homozygous W748S mutation in affected members from 2 families with a form of SANDO characterized by early onset of migraine headaches and/or seizures, and the later development of myoclonus (see SCAE; 607459). Both patients were also homozygous for another putative disease-causing POLG mutation (Q497H; 174763.0016). In 4 children with mitochondrial DNA depletion syndrome-4A (203700), manifest as Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene: W748S and G848S (174763.0006). All patients died in childhood. Nguyen et al. (2005) reported a patient with Alpers syndrome who was compound heterozygous for G848S and W748S. Hakonen et al. (2007) demonstrated that the disease W748S haplotype in patients from Australia and New Zealand derived from a common European haplotype. This haplotype shared a long region with the Finnish and Norwegian haplotype, but differed from Belgian and British patients, suggesting that the founder who formed the isolate in Australia and New Zealand may have been of Scandinavian rather than British origin. Hakonen et al. (2007) estimated that the common ancestor for the W748S haplotype lived more than 40 to 60 generations ago, before 1200 to 800 A.D. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931520.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001953092.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001967093.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(May 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
POLG-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004772400.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related … (more)
The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Apr 07, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Mitochondrial disease
Affected status: yes
Allele origin:
germline
|
Wellcome Centre for Mitochondrial Research, Newcastle University
Accession: SCV000575916.1
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Number of individuals with the variant: 1
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742213.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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not provided
(-)
|
no classification provided
Method: literature only
|
Mitochondrial disease
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040909.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
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not provided
(-)
|
no classification provided
Method: phenotyping only
|
Not Provided
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV002075066.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance … (more)
Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. 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:
Number of individuals with the variant: 1
Clinical Features:
Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Hearing impairment (present) … (more)
Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Hearing impairment (present) , Tinnitus (present) , Abnormal large intestine morphology (present) (less)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-11-07
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized … (more)
Abnormality of the nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized hypotonia (present) , Seizure (present) , Autistic behavior (present) , Abnormal aggressive, impulsive or violent behavior (present) , Anxiety (present) , Hypohidrosis (present) , Abnormal muscle physiology (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-01-03
Testing laboratory interpretation: Uncertain significance
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Pathogenic
(Mar 19, 2018)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000809069 appears to be redundant with SCV000802086.
(less)
Notes: SCV000809069 appears to
(...more)
Source: NCBI
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Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Affected status: unknown
Allele origin:
paternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000809069.2
First in ClinVar: Oct 11, 2015 Last updated: May 27, 2023 |
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| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447)
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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.
Comment:
Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). 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. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It is commonly reported in individuals of Finnish ancestry. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). This variant is reported with the allele frequency (0.09%) in the gnomAD Exomes. It is submitted to ClinVar as uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen – score1.00; Sift – score 0.01; Mutation Taster – score 1.00). The amino acid Trptophan at position 748 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp748Ser in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4
Comment:
This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268).
Comment:
Criteria applied: PS3,PM3_STR,PS4_MOD,PP3
Comment:
The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2243, causing the tryptophan (W) at amino acid position 748 to be replaced by a serine (S). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.099% (280/282688) total alleles studied. The highest observed frequency was 0.621% (156/25104) of European (Finnish) alleles. The c.2243G>C (p.W748S) alteration accounts for approximately 8% of disease causing alleles in the Finnish population. This alteration has been identified in the homozygous state and in conjunction with another alteration in POLG in multiple individuals with Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO), and other autosomal recessive POLG-related mitochondrial disorders (Bychkov, 2021; Masingue, 2019; Henao, 2016; Hakonen, 2007; Janssen, 2016; Uusimaa, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Comment:
The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic.
Comment:
Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. 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:
Across a selection of available literature, the c.2243G>C (p.Trp748Ser) variant has been identified in a total of 86 patients with POLG-related spectrum disorders including 52 in a homozygous state, 31 in a compound heterozygous state, and three in a heterozygous state (Van Goethem et al. 2004; Hakonen et al. 2005; Tzoulis et al. 2006; Tang et al. 2012). Several of these studies indicate that this variant appears to be in cis with a second missense variant, c.3428A>G (p.Glu1143Gly), which is a relatively common variant suggested by Hankonen et al. (2005) to be a polymorphism. The p.Trp748Ser variant has also been detected in a heterozygous state in unaffected family members (Van Goethem et al. 2004). This p.Trp748Ser variant was reported in two of 976 control chromosomes and at a frequency of 0.00566 in the European (Finnish) population of the Exome Aggregation Consortium. Tang et al. (2012) suggest that the Trp248 residue is evolutionarily conserved. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). Both studies showed a decrease in binding affinity of DNA polymerase to DNA in the presence of the p.Trp748Ser variant, at 1.6-fold and 8-fold reduction, respectively. Based on the collective evidence, the p.Trp748Ser variant is classified as pathogenic for POLG-related spectrum disorders.
Comment:
The p.Trp748Ser variant in POLG has been reported in the homozygous or compound heterozygous state in >20 individuals with POLG-related mitochondrial disorders (Tang 2011, Brunetti-Pierri 2008, Tzoulis 2009, Nicastro 2016, Arkadir 2015, Leh mann 2016). This variant has also been reported in ClinVar (Variation ID# 13507) and has been identified in 0.636% (164/25774) of Finnish chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). However, th is frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Trp748Ser variant m ay impact protein function (Chan 2006); however, these types of assays may not a ccurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for POLG-related mitochondrial disorders in an a utosomal recessive manner based upon presence in affected individuals and functi onal evidence. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PP3.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP1,PP3,PP4.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20691285, 21956653, 21455106, 25713120, 21880868, 22616202, 20438629, 25025039, 22189570, 25497598, 21515089, 23448099, 23808377, 21993618, 23212759, 22166854, 20576279, 20818383, 21236670, 22931735, 25585994, 15477547, 17088268, 24841123, 20153822, 26755490, 27290639, 28130605, 27450679, 26104464, 27822509, 23248042, 26607151, 26942291, 15824347, 18991199, 29482223, 28471437, 18546343, 18321754, 24725338, 19566497, 18294203, 24122062, 30306720, 29655203, 30423451, 31164858, 27422324, 30860128, 30843307, 31980526, 31475037, 32445240, 33469851, 33300680, 32964447)
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This is the second most common pathogenic POLG variant, accounting for approximately 8% of disease-causing alleles (PMID: 20301791, 21880868). This variant segregates with disease in multiple families. 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.
Comment:
Variant summary: POLG c.2243G>C (p.Trp748Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251290 control chromosomes. c.2243G>C has been reported in the literature in multiple individuals affected with POLG-Related Spectrum Disorders as both homozygote and compound heterozygote genotypes (e.g. Tzoulis_2006). 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. The most pronounced variant effect results in <10% of normal activity (e.g. Chan_2006). The following publications have been ascertained in the context of this evaluation (PMID: 17088268, 16638794). 29 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=25), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 748 of the POLG protein (p.Trp748Ser). This variant is present in population databases (rs113994097, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive POLG-related disease (PMID: 15477547, 16080118, 16638794, 17894835, 18294203, 18546343, 22166854, 22931735). It is commonly reported in individuals of Finnish ancestry (PMID: 16080118). ClinVar contains an entry for this variant (Variation ID: 13507). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on POLG function (PMID: 17088268, 20153822). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
The missense c.2243G>C (p.Trp748Ser) in the POLG gene has been observed in individual(s) with autosomal recessive POLG-related disease (Chan, Sherine S L et al.,2006). It is commonly reported in individuals of Finnish ancestry. Functional studies have been conducted to evaluate the role of the p.Trp748Ser variant on DNA polymerase catalytic activity and binding affinity. Expression of DNA polymerase with wild-type or variant p.Trp748Ser cDNA in baculovirus-infected Sf9 cells showed a decrease in catalytic activity compared to wild type (Chan et al. 2006), but this was not observed in another study (Palin et al. 2012). This variant is reported with the allele frequency (0.09%) in the gnomAD Exomes. It is submitted to ClinVar as uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen – score1.00; Sift – score 0.01; Mutation Taster – score 1.00). The amino acid Trptophan at position 748 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp748Ser in POLG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
The NM_002693.2:c.2243G>C (NP_002684.1:p.Trp748Ser) [GRCH38: NC_000015.10:g.89323426C>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:17088268 ; 21880868 . 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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.099%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013507). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 18991199). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 18991199). A different missense change at the same codon (p.Trp748Cys) has been reported to be associated with POLG-related disorder (PMID: 26169155). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant was identified as compound heterozygous with NM_002693.3:c.2901_2907del._x000D_ Criteria applied: PM3_VSTR, PS3, PP4
Comment:
This variant is interpreted as Pathogenic for Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE). The following ACMG Tag(s) were applied: PM2 =>Absent from controls (or at extremely low frequency if recessive) in gnomAD. PM3_very strong => For recessive disorders, detected in trans with a pathogenic variant (PMID: 15477547; 15929042; 15824347; 18828154; 19578034). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:15477547). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-moderate => Well-established functional studies show a deleterious effect (PMID:17088268).
Comment:
Criteria applied: PS3,PM3_STR,PS4_MOD,PP3
Comment:
The c.2243G>C (p.W748S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a G to C substitution at nucleotide position 2243, causing the tryptophan (W) at amino acid position 748 to be replaced by a serine (S). Based on the available evidence, this alteration is classified as pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.099% (280/282688) total alleles studied. The highest observed frequency was 0.621% (156/25104) of European (Finnish) alleles. The c.2243G>C (p.W748S) alteration accounts for approximately 8% of disease causing alleles in the Finnish population. This alteration has been identified in the homozygous state and in conjunction with another alteration in POLG in multiple individuals with Alpers-Huttenlocher syndrome (AHS), sensory ataxic neuropathy, dysarthria/dysphagia, and external ophthalmoplegia (SANDO), and other autosomal recessive POLG-related mitochondrial disorders (Bychkov, 2021; Masingue, 2019; Henao, 2016; Hakonen, 2007; Janssen, 2016; Uusimaa, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
POLG: PM3:Very Strong, PM2, PP3, PS3:Supporting
Comment:
The POLG c.2243G>C variant is predicted to result in the amino acid substitution p.Trp748Ser. This variant has been documented as pathogenic for autosomal recessive POLG-related disorders (Tang et al. 2011. PubMed ID: 21880868). It is a common founder variant for autosomal recessive progressive ataxia in the Finnish population (Hakonen et al. 2005. PubMed ID: 16080118). This variant is reported in 0.62% of alleles in individuals of European (Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic.
Comment:
Variant identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 11-07-2019 by Lab or GTR ID 26957. Variant interpreted as Uncertain significance and reported on 01-03-2018 by Lab or GTR ID 500031. 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 |
| Mitochondrial DNA maintenance disorders in 102 patients from different parts of Russia: Mutational spectrum and phenotypes. | Bychkov IO | Mitochondrion | 2021 | PMID: 33486010 |
| Clinico-pathological and Molecular Spectrum of Mitochondrial Polymerase γ Mutations in a Cohort from India. | Deepha S | Journal of molecular neuroscience : MN | 2021 | PMID: 33469851 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Comprehensive Genetic Analysis of a Hungarian Amyotrophic Lateral Sclerosis Cohort. | Tripolszki K | Frontiers in genetics | 2019 | PMID: 31475037 |
| Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy. | Demos M | Frontiers in neurology | 2019 | PMID: 31164858 |
| Complex heterozygous polymerase gamma mutation and cerebral folate deficiency in a child with refractory partial status. | Samanta D | Neurology India | 2019 | PMID: 30860128 |
| POLG mutations presenting as Charcot-Marie-Tooth disease. | Phillips J | Journal of the peripheral nervous system : JPNS | 2019 | PMID: 30843307 |
| The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort. | Piekutowska-Abramczuk D | Mitochondrion | 2019 | PMID: 30423451 |
| Dissecting the neuronal vulnerability underpinning Alpers' syndrome: a clinical and neuropathological study. | Hayhurst H | Brain pathology (Zurich, Switzerland) | 2019 | PMID: 30021052 |
| Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. | Masingue M | Mitochondrion | 2019 | PMID: 29474836 |
| Mitochondrial disease and amyloidosis in a patient with familial polyneuropathy. | Gebus O | European journal of neurology | 2018 | PMID: 30306720 |
| Elevated cerebrospinal fluid protein in POLG-related epilepsy: Diagnostic and prognostic implications. | Hikmat O | Epilepsia | 2018 | PMID: 29920680 |
| Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. | Peeva V | Nature communications | 2018 | PMID: 29712893 |
| Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
| Mitochondrial POLG related disorder presenting prenatally with fetal cerebellar growth arrest. | Inbar-Feigenberg M | Metabolic brain disease | 2018 | PMID: 29574624 |
| Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes. | Coutelier M | JAMA neurology | 2018 | PMID: 29482223 |
| Targeted versus untargeted omics - the CAFSA story. | Del Mar Amador M | Journal of inherited metabolic disease | 2018 | PMID: 29423831 |
| Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants. | Castiglioni C | European journal of human genetics : EJHG | 2018 | PMID: 29358615 |
| Outcome of epilepsy in patients with mitochondrial disorders: Phenotype genotype and magnetic resonance imaging correlations. | Bindu PS | Clinical neurology and neurosurgery | 2018 | PMID: 29272804 |
| The presence of anaemia negatively influences survival in patients with POLG disease. | Hikmat O | Journal of inherited metabolic disease | 2017 | PMID: 28865037 |
| Decreased male reproductive success in association with mitochondrial dysfunction. | Martikainen MH | European journal of human genetics : EJHG | 2017 | PMID: 28812649 |
| Speech and swallowing abnormalities in adults with POLG associated ataxia (POLG-A). | Vogel AP | Mitochondrion | 2017 | PMID: 28634151 |
| 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 |
| Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase γ: Novel Mechanisms of Function and Pathogenesis. | Euro L | Biochemistry | 2017 | PMID: 28206745 |
| Novel POLG mutations and variable clinical phenotypes in 13 Italian patients. | Da Pozzo P | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2017 | PMID: 28130605 |
| No evidence of ischemia in stroke-like lesions of mitochondrial POLG encephalopathy. | Tzoulis C | Mitochondrion | 2017 | PMID: 27838477 |
| Late-onset of Alpers-Huttenlocher syndrome: an unusual cause of refractory epilepsy and liver failure. | London F | Acta neurologica Belgica | 2017 | PMID: 27422324 |
| Peripheral neuropathy in patients with CPEO associated with single and multiple mtDNA deletions. | Lehmann D | Neurology. Genetics | 2016 | PMID: 27822509 |
| New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. | Pronicka E | Journal of translational medicine | 2016 | PMID: 27290639 |
| PRICKLE2 Mutations Might Not Be Involved in Epilepsy. | Sandford E | American journal of human genetics | 2016 | PMID: 26942291 |
| Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation. | Henao AI | The neuroradiology journal | 2016 | PMID: 26755490 |
| Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation. | Nicastro N | Cerebellum (London, England) | 2016 | PMID: 26607151 |
| The spectrum of epilepsy caused by POLG mutations. | Janssen W | Acta neurologica Belgica | 2016 | PMID: 26104464 |
| Novel POLG mutation in a patient with sensory ataxia, neuropathy, ophthalmoparesis and stroke. | Lam CW | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 26169155 |
| Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease. | Kaliszewska M | Human genetics | 2015 | PMID: 26077851 |
| Teaching NeuroImages: hypertrophic olivary degeneration in a young man with POLG gene mutation. | Arkadir D | Neurology | 2015 | PMID: 25713120 |
| Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson's disease. | Gui YX | Parkinsonism & related disorders | 2015 | PMID: 25585994 |
| Exome sequencing in undiagnosed inherited and sporadic ataxias. | Pyle A | Brain : a journal of neurology | 2015 | PMID: 25497598 |
| Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. | Høyer H | BioMed research international | 2014 | PMID: 25025039 |
| Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts. | Sitarz KS | Molecular genetics and metabolism | 2014 | PMID: 24725338 |
| Variations of mitochondrial DNA polymerase γ in patients with Parkinson's disease. | Ylönen S | Journal of neurology | 2013 | PMID: 24122062 |
| Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings. | Gaily E | Epilepsia | 2013 | PMID: 23808377 |
| Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features. | Uusimaa J | Epilepsia | 2013 | PMID: 23448099 |
| POLG mutation presenting with late-onset jerky torticollis. | Tuladhar AM | Journal of neurology | 2013 | PMID: 23212759 |
| Successful treatment of POLG-related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet. | Martikainen MH | Epileptic disorders : international epilepsy journal with videotape | 2012 | PMID: 23248042 |
| Early-onset ataxia with progressive external ophthalmoplegia associated with POLG mutation: autosomal recessive mitochondrial ataxic syndrome or SANDO? | Habek M | The neurologist | 2012 | PMID: 22931735 |
| Screening for POLG W748S and A467T mutations in ataxia patients from Spain. | Pelayo-Negro AL | Movement disorders : official journal of the Movement Disorder Society | 2012 | PMID: 22711370 |
| Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. | Lax NZ | Brain : a journal of neurology | 2012 | PMID: 22189570 |
| Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia. | Palin EJ | Journal of the neurological sciences | 2012 | PMID: 22166854 |
| Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations. | Tang S | Journal of neurology | 2012 | PMID: 21993618 |
| Dystonia in mitochondrial spinocerebellar ataxia and epilepsy syndrome associated with novel recessive POLG mutations. | Hinnell C | Movement disorders : official journal of the Movement Disorder Society | 2012 | PMID: 21956653 |
| 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 |
| Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. | Tang S | Journal of medical genetics | 2011 | PMID: 21880868 |
| Parieto-occipital lobe epilepsy caused by a POLG1 compound heterozygous A467T/W748S genotype. | Roshal D | Epilepsy & behavior : E&B | 2011 | PMID: 21515089 |
| Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene. | Pronicka E | Medical science monitor : international medical journal of experimental and clinical research | 2011 | PMID: 21455106 |
| Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye. | Smits BW | Neuromuscular disorders : NMD | 2011 | PMID: 21236670 |
| POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome. | Mousson de Camaret B | Mitochondrion | 2011 | PMID: 20691285 |
| High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
| [Mitochondrial DNA depletion and POLG mutations in a patient with sensory ataxia, dysarthria and ophthalmoplegia]. | Posada IJ | Medicina clinica | 2010 | PMID: 20576279 |
| POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype. | Komulainen T | BMC neurology | 2010 | PMID: 20438629 |
| Functional analysis of H. sapiens DNA polymerase gamma spacer mutation W748S with and without common variant E1143G. | Palin EJ | Biochimica et biophysica acta | 2010 | PMID: 20153822 |
| A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes. | Kurt B | Archives of neurology | 2010 | PMID: 20142534 |
| Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations. | Schulte C | Neurology | 2009 | PMID: 19752458 |
| The unfolding clinical spectrum of POLG mutations. | Blok MJ | Journal of medical genetics | 2009 | PMID: 19578034 |
| Mitochondrial DNA depletion in progressive external ophthalmoplegia caused by POLG1 mutations. | Tzoulis C | Acta neurologica Scandinavica. Supplementum | 2009 | PMID: 19566497 |
| Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. | Stewart JD | Journal of medical genetics | 2009 | PMID: 19251978 |
| Clinical and molecular features of mitochondrial DNA depletion syndromes. | Spinazzola A | Journal of inherited metabolic disease | 2009 | PMID: 19125351 |
| MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome. | Naess K | Biochimica et biophysica acta | 2009 | PMID: 19103152 |
| Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. | Taanman JW | Human mutation | 2009 | PMID: 18828154 |
| Rapidly progressive neurological deterioration in a child with Alpers syndrome exhibiting a previously unremarkable brain MRI. | Brunetti-Pierri N | Neuropediatrics | 2008 | PMID: 18991199 |
| Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. | Wong LJ | Human mutation | 2008 | PMID: 18546365 |
| Apraxia of lid opening mimicking ptosis in compound heterozygosity for A467T and W748S POLG1 mutations. | Paus S | Movement disorders : official journal of the Movement Disorder Society | 2008 | PMID: 18546343 |
| Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. | Ashley N | Human molecular genetics | 2008 | PMID: 18487244 |
| Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. | Remes AM | Parkinsonism & related disorders | 2008 | PMID: 18321754 |
| Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. | Uusimaa J | Epilepsia | 2008 | PMID: 18294203 |
| Do carriers of POLG mutation W748S have disease manifestations? | Rantamäki M | Clinical genetics | 2007 | PMID: 17894835 |
| Mitochondrial DNA depletion is a prevalent cause of multiple respiratory chain deficiency in childhood. | Sarzi E | The Journal of pediatrics | 2007 | PMID: 17452231 |
| The A467T and W748S POLG substitutions are a rare cause of adult-onset ataxia in Europe. | Craig K | Brain : a journal of neurology | 2007 | PMID: 17438011 |
| 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 |
| Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphismin mitochondrial disorders. | Chan SS | Human molecular genetics | 2006 | PMID: 17088268 |
| Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. | Naïmi M | European journal of human genetics : EJHG | 2006 | PMID: 16639411 |
| The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. | Tzoulis C | Brain : a journal of neurology | 2006 | PMID: 16638794 |
| Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. | Horvath R | Brain : a journal of neurology | 2006 | PMID: 16621917 |
| Molecular diagnosis of Alpers syndrome. | Nguyen KV | Journal of hepatology | 2006 | PMID: 16545482 |
| POLG mutations in Alpers syndrome. | Nguyen KV | Neurology | 2005 | PMID: 16177225 |
| Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. | Hakonen AH | American journal of human genetics | 2005 | PMID: 16080118 |
| POLG mutations and Alpers syndrome. | Davidzon G | Annals of neurology | 2005 | PMID: 15929042 |
| Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. | Winterthun S | Neurology | 2005 | PMID: 15824347 |
| Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. | Ferrari G | Brain : a journal of neurology | 2005 | PMID: 15689359 |
| POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. | Van Goethem G | Neurology | 2004 | PMID: 15477547 |
| Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family. | Rantamäki M | Neurology | 2001 | PMID: 11571332 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs113994097 ...
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Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.