The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.803G>C (p.Gly268Ala)
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.
(20)
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.
Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(2); Likely benign(7)
Uncertain significance(8); Benign(2); Likely benign(7)
20
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002693.3(POLG):c.803G>C (p.Gly268Ala)
Variation ID: 196354 Accession: VCV000196354.70
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q26.1 15: 89330133 (GRCh38) [ NCBI UCSC ] 15: 89873364 (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 Jan 30, 2017 Jan 19, 2025 Nov 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002693.3:c.803G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Gly268Ala missense NM_001126131.2:c.803G>C NP_001119603.1:p.Gly268Ala missense NC_000015.10:g.89330133C>G NC_000015.9:g.89873364C>G NG_008218.2:g.9663G>C LRG_765:g.9663G>C LRG_765t1:c.803G>C LRG_765p1:p.Gly268Ala P54098:p.Gly268Ala - Protein change
- G268A
- Other names
-
p.G268A:GGG>GCG
- Canonical SPDI
- NC_000015.10:89330132: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.
-
0.00280 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00250
1000 Genomes Project 0.00280
The Genome Aggregation Database (gnomAD), exomes 0.00344
Exome Aggregation Consortium (ExAC) 0.00348
The Genome Aggregation Database (gnomAD) 0.00364
Trans-Omics for Precision Medicine (TOPMed) 0.00369
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00385
- 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 |
2023 | 3036 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Feb 22, 2024 | RCV000177165.25 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000233823.22 | |
| Conflicting classifications of pathogenicity (5) |
criteria provided, conflicting classifications
|
Nov 1, 2024 | RCV000415771.55 | |
| Likely benign (2) |
no assertion criteria provided
|
Apr 15, 2021 | RCV000709833.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 11, 2021 | RCV000768291.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001121511.12 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 8, 2021 | RCV001847817.11 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 22, 2020 | RCV002312719.9 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Sep 15, 2024 | RCV002227084.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 1, 2022 | RCV002516726.9 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Sep 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000596506.1
First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017 |
|
|
|
Likely benign
(Feb 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610284.1
First in ClinVar: Jan 30, 2017 Last updated: Jan 30, 2017 |
|
|
|
Likely benign
(Jan 30, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228997.5
First in ClinVar: Jun 28, 2015 Last updated: Oct 19, 2018 |
Sex: mixed
|
|
|
Benign
(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: SCV000887103.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
Comment:
The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been … (more)
The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. (less)
|
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139685.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-Related Spectrum Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001280136.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Uncertain significance
(Dec 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802094.2
First in ClinVar: Aug 04, 2018 Last updated: Jun 02, 2021 |
Number of individuals with the variant: 3
|
|
|
Uncertain significance
(Nov 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002104888.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Uncertain significance
(Jul 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000242265.15
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether … (more)
Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentified pathogenic variant in POLG or another gene that was not detected by the testing methods (Blok et al., 2009; Tang et al. 2011); Pathogenicity of G268A was questioned as the G268A variant was present at high frequency in this cohort; however, it was not found with another POLG pathogenic variant in any of the patients (Tang et al., 2011); Functional studies are discordant regarding the effect of this variant; those studies using the yeast homologue demonstrate a deleterious effect, while those using human POLG demonstrate no significant effect (Baruffini et al., 2006; Baruffini et al., 2015; Macao et al., 2015; Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenic variants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database); This variant is associated with the following publications: (PMID: 14635118, 26095671, 25462018, 16940310, 26357557, 21880868, 19578034, 24508722, 16401742, 25118206, 27987238, 28128857, 29474836, 31139930, 30637288, 32391929, 34023347, 32949115) (less)
|
|
|
Uncertain significance
(Nov 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
Mitochondrial DNA depletion syndrome 4b Progressive sclerosing poliodystrophy Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898903.2
First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023 |
Comment:
POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias … (more)
POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain. (less)
|
|
|
Uncertain significance
(Jun 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003809206.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241129.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain of the encoded protein sequence. … (more)
Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 1614062 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), suggesting that the variant is benign. c.803G>C has been reported in the literature in individuals affected with progressive external ophthalmoplegia in the homozygous state (DiFonzo_POLG_HM_2003, DelBo_2003) and in patients suggestive POLG deficiency (Tang_2015) as well as unspecified mitochondrial disorders (Cruz_2017). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. Experimental evidence involving the variant has been conflicting, with some yeast and cell transfection studies showing a damaging effect while other studies in human cells showed remaining functional activity (Baruffini_2006, Kasahara_2016, Baruffini_2015). The following publications have been ascertained in the context of this evaluation (PMID: 14635118, 16940310, 27987238, 21880868, 28128857, 25462018). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including 8 VUS, 8 likely benign/benign and 1 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000287674.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Jan 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000846687.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(Nov 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493481.34
First in ClinVar: Jan 30, 2017 Last updated: Dec 22, 2024 |
Comment:
POLG: BS2
Number of individuals with the variant: 55
|
|
|
likely benign
(Feb 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000614735.5
First in ClinVar: Dec 19, 2017 Last updated: Jan 19, 2025 |
|
|
|
Uncertain significance
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease axonal type 2U
Affected status: yes
Allele origin:
unknown
|
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV003035490.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
|
|
|
Likely benign
(Apr 15, 2021)
|
no assertion criteria provided
Method: clinical testing
|
POLG-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004738686.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
POLG-Related disorder
Affected status: unknown
Allele origin:
germline
|
GenomeConnect, ClinGen
Accession: SCV000840162.1
First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018 |
Comment:
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 … (more)
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)
Clinical Features:
Ptosis (present) , Hypermetropia (present) , Abnormality of the lens (present) , Increased susceptibility to fractures (present) , Abnormality of the curvature of the vertebral … (more)
Ptosis (present) , Hypermetropia (present) , Abnormality of the lens (present) , Increased susceptibility to fractures (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Abnormality of the intestine (present) , Abnormality of esophagus morphology (present) , Neoplasm of the skin (present) (less)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-10-13
Testing laboratory interpretation: Uncertain significance
|
|
|
Likely pathogenic
(Oct 01, 2021)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Claim with insufficient supporting evidence
Notes: This gene has insufficient supporting evidence for isolated Tip-Toe Gait.
(less)
Notes: This gene has
(...more)
Source: ClinGen
|
Tip-toe gait
Affected status: yes
Allele origin:
germline
|
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV002506570.2
First in ClinVar: May 07, 2022 Last updated: Jun 23, 2024 |
Comment:
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, … (more)
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. (less)
Clinical Features:
Pes cavus (present) , Clinodactyly (present) , Pectus excavatum (present) , Delayed speech and language development (present) , limited range of motion of upper ankle … (more)
Pes cavus (present) , Clinodactyly (present) , Pectus excavatum (present) , Delayed speech and language development (present) , limited range of motion of upper ankle (present) (less)
Age: 0-9 years
Sex: male
Method: Gene panel analysis
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentified pathogenic variant in POLG or another gene that was not detected by the testing methods (Blok et al., 2009; Tang et al. 2011); Pathogenicity of G268A was questioned as the G268A variant was present at high frequency in this cohort; however, it was not found with another POLG pathogenic variant in any of the patients (Tang et al., 2011); Functional studies are discordant regarding the effect of this variant; those studies using the yeast homologue demonstrate a deleterious effect, while those using human POLG demonstrate no significant effect (Baruffini et al., 2006; Baruffini et al., 2015; Macao et al., 2015; Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenic variants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database); This variant is associated with the following publications: (PMID: 14635118, 26095671, 25462018, 16940310, 26357557, 21880868, 19578034, 24508722, 16401742, 25118206, 27987238, 28128857, 29474836, 31139930, 30637288, 32391929, 34023347, 32949115)
Comment:
POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain.
Comment:
Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 1614062 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), suggesting that the variant is benign. c.803G>C has been reported in the literature in individuals affected with progressive external ophthalmoplegia in the homozygous state (DiFonzo_POLG_HM_2003, DelBo_2003) and in patients suggestive POLG deficiency (Tang_2015) as well as unspecified mitochondrial disorders (Cruz_2017). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. Experimental evidence involving the variant has been conflicting, with some yeast and cell transfection studies showing a damaging effect while other studies in human cells showed remaining functional activity (Baruffini_2006, Kasahara_2016, Baruffini_2015). The following publications have been ascertained in the context of this evaluation (PMID: 14635118, 16940310, 27987238, 21880868, 28128857, 25462018). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including 8 VUS, 8 likely benign/benign and 1 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
POLG: BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Comment:
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:
The NM_002693.2:c.803G>C (NP_002684.1:p.Gly268Ala) [GRCH38: NC_000015.10:g.89330133C>G] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16940310 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Unclear whether patients found to harbor a single G268A variant were incidentally found to be carriers of an autosomal recessive POLG pathogenic variant or whether they may have a second unidentified pathogenic variant in POLG or another gene that was not detected by the testing methods (Blok et al., 2009; Tang et al. 2011); Pathogenicity of G268A was questioned as the G268A variant was present at high frequency in this cohort; however, it was not found with another POLG pathogenic variant in any of the patients (Tang et al., 2011); Functional studies are discordant regarding the effect of this variant; those studies using the yeast homologue demonstrate a deleterious effect, while those using human POLG demonstrate no significant effect (Baruffini et al., 2006; Baruffini et al., 2015; Macao et al., 2015; Kasahara et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variant alters a highly conserved position in the exonuclease domain of the protein where many missense pathogenic variants have been reported in association with POLG-related disorders (Human DNA Polymerase Gamma Mutation Database); This variant is associated with the following publications: (PMID: 14635118, 26095671, 25462018, 16940310, 26357557, 21880868, 19578034, 24508722, 16401742, 25118206, 27987238, 28128857, 29474836, 31139930, 30637288, 32391929, 34023347, 32949115)
Comment:
POLG NM_002693.2 exon 3 p.Gly268Ala (c.803G>C): This variant has been reported in several individuals with clinical suspicion of POLG related conditions, including progressive external ophthalmoplegias (PEO) (Di Fonzo 2003 PMID:14635118, Del Bo 2003 PMID:14557557, Gonzalez-Vioque 2006 PMID:16401742, Tang 2011 PMID:21880868). Individuals reported in the literature present with this variant in the heterozygous and homozygous state, but the clinical impact of zygosity is unclear. This variant is present in 0.4% (534/126574) of European individuals, including 3 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs61752784). This variant is present in ClinVar (Variation ID:196354). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In vitro functional studies suggest a deleterious effect of this variant. However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Furthermore, at least one publication has questioned the pathogenicity of this variant (Tang 2011 PMID:21880868). This, combined with the high minor allele frequency identified in controls, conflicts with the expected pathogenicity of this variant. Therefore, the clinical significance of this variant is uncertain.
Comment:
Variant summary: POLG c.803G>C (p.Gly268Ala) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 1614062 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related phenotype (0.0035), suggesting that the variant is benign. c.803G>C has been reported in the literature in individuals affected with progressive external ophthalmoplegia in the homozygous state (DiFonzo_POLG_HM_2003, DelBo_2003) and in patients suggestive POLG deficiency (Tang_2015) as well as unspecified mitochondrial disorders (Cruz_2017). These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial DNA Depletion Syndrome - POLG Related. Experimental evidence involving the variant has been conflicting, with some yeast and cell transfection studies showing a damaging effect while other studies in human cells showed remaining functional activity (Baruffini_2006, Kasahara_2016, Baruffini_2015). The following publications have been ascertained in the context of this evaluation (PMID: 14635118, 16940310, 27987238, 21880868, 28128857, 25462018). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including 8 VUS, 8 likely benign/benign and 1 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
POLG: BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.
Comment:
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 |
|---|---|---|---|---|
| NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly. | Pomarino D | Global medical genetics | 2023 | PMID: 37091313 |
| Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset. | Rossetti R | Frontiers in endocrinology | 2021 | PMID: 34803902 |
| Klinefelter's Syndrome with Maternal Uniparental Disomy X, Interstitial Xp22.31 Deletion, X-linked Ichthyosis, and Severe Central Nervous System Regression. | Brault J | Journal of pediatric genetics | 2021 | PMID: 34504726 |
| Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing. | Fang LT | Nature biotechnology | 2021 | PMID: 34504347 |
| Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology. | Hegarty R | The Journal of pediatrics | 2021 | PMID: 34023347 |
| The impact of gender, puberty, and pregnancy in patients with POLG disease. | Hikmat O | Annals of clinical and translational neurology | 2020 | PMID: 32949115 |
| Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. | Masingue M | Mitochondrion | 2019 | PMID: 29474836 |
| Late-onset Levodopa Responsive Parkinsonism Due to Polymerase γ 1 Mutations. | Calejo M | Movement disorders clinical practice | 2018 | PMID: 30637288 |
| Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. | McWilliams TG | Open biology | 2018 | PMID: 30404819 |
| Clinical, biochemical, molecular, and histological features of 65 Portuguese patients with mitochondrial disorders. | Cruz S | Muscle & nerve | 2017 | PMID: 28128857 |
| Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. | Kasahara T | Psychiatry and clinical neurosciences | 2017 | PMID: 27987238 |
| Mitochondrial DNA Variation and Heteroplasmy in Monozygotic Twins Clinically Discordant for Multiple Sclerosis. | Souren NY | Human mutation | 2016 | PMID: 27119776 |
| Rigid Spine Syndrome among Children in Oman. | Koul R | Sultan Qaboos University medical journal | 2015 | PMID: 26357557 |
| The exonuclease activity of DNA polymerase γ is required for ligation during mitochondrial DNA replication. | Macao B | Nature communications | 2015 | PMID: 26095671 |
| Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae. | Baruffini E | Mitochondrion | 2015 | PMID: 25462018 |
| A diagnostic flow chart for POLG-related diseases based on signs sensitivity and specificity. | Tchikviladzé M | Journal of neurology, neurosurgery, and psychiatry | 2015 | PMID: 25118206 |
| Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes. | Farnum GA | Biochimica et biophysica acta | 2014 | PMID: 24508722 |
| Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort. | Rouzier C | European journal of human genetics : EJHG | 2014 | PMID: 23921535 |
| Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. | Tang S | Journal of medical genetics | 2011 | PMID: 21880868 |
| The unfolding clinical spectrum of POLG mutations. | Blok MJ | Journal of medical genetics | 2009 | PMID: 19578034 |
| Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. | Wong LJ | Human mutation | 2008 | PMID: 18546365 |
| Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. | Baruffini E | Human molecular genetics | 2006 | PMID: 16940310 |
| Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. | González-Vioque E | Archives of neurology | 2006 | PMID: 16401742 |
| POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. | Di Fonzo A | Human mutation | 2003 | PMID: 14635118 |
| Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. | Del Bo R | Neurology | 2003 | PMID: 14557557 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs61752784 ...
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Record last updated Jan 19, 2025
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.