ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.915C>G (p.Ser305Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.915C>G (p.Ser305Arg)
Variation ID: 206588 Accession: VCV000206588.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89329051 (GRCh38) [ NCBI UCSC ] 15: 89872282 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 9, 2016 Oct 8, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.915C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Ser305Arg missense NM_001126131.2:c.915C>G NP_001119603.1:p.Ser305Arg missense NC_000015.10:g.89329051G>C NC_000015.9:g.89872282G>C NG_008218.2:g.10745C>G LRG_765:g.10745C>G LRG_765t1:c.915C>G LRG_765p1:p.Ser305Arg - Protein change
- S305R
- Other names
- p.S305R:AGC>AGG
- Canonical SPDI
- NC_000015.10:89329050:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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POLG | - | - |
GRCh38 GRCh37 |
1864 | 3006 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV000188649.26 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000758271.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2019 | RCV000995844.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2020 | RCV001332170.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 30, 2020 | RCV002372152.3 |
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
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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. |
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Likely pathogenic
(Oct 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000886923.1
First in ClinVar: Mar 11, 2019 Last updated: Mar 11, 2019 |
Comment:
The NM_002693.2:c.915C>G (NP_002684.1:p.Ser305Arg) [GRCH38: NC_000015.10:g.89329051G>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has … (more)
The NM_002693.2:c.915C>G (NP_002684.1:p.Ser305Arg) [GRCH38: NC_000015.10:g.89329051G>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:19578034 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic. (less)
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Pathogenic
(Jun 06, 2019)
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criteria provided, single submitter
Method: clinical testing
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150221.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Mar 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001524403.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID 19578034 etc.]
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Pathogenic
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000242272.12
First in ClinVar: Aug 07, 2015 Last updated: Jul 16, 2023 |
Comment:
Published functional studies demonstrate reduced DNA affinity and nucleotide mismatch excision rate, leading to a reduction in mtDNA content and increase in mtDNA mutation frequency … (more)
Published functional studies demonstrate reduced DNA affinity and nucleotide mismatch excision rate, leading to a reduction in mtDNA content and increase in mtDNA mutation frequency (Qian et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22000311, 19578034, 21824913, 18546365, 21880868, 25914719, 20883824, 30860128) (less)
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Pathogenic
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205881.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001377915.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 305 of the POLG protein (p.Ser305Arg). … (more)
This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 305 of the POLG protein (p.Ser305Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 19578034, 20883824, 22000311). ClinVar contains an entry for this variant (Variation ID: 206588). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. Experimental studies have shown that this missense change affects POLG function (PMID: 20883824, 25914719, 26095671). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002684842.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S305R variant (also known as c.915C>G), located in coding exon 3 of the POLG gene, results from a C to G substitution at nucleotide … (more)
The p.S305R variant (also known as c.915C>G), located in coding exon 3 of the POLG gene, results from a C to G substitution at nucleotide position 915. The serine at codon 305 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in three individuals with Alpers syndrome who also carried POLG p.A467T (phase was not confirmed) (Hunter MF et al. Pediatr. Neurol., 2011 Nov;45:311-8; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Hakonen AH et al. Eur. J. Hum. Genet., 2007 Jul;15:779-83) as well as in one individual with Alpers syndrome without a second identifiable alteration (Wong LJ et al. Hum. Mutat., 2008 Sep;29:E150-72). In addition, this alteration was detected in one individual with generalized seizures, myoclonic jerks, ataxia, and sensory-axonal peripheral neuropathy who also carried POLG p.R627Q and in one individual with muscular hypotonia, status epilepticus, repeated vomiting, severe lactic acidosis, and liver failure who may have also carried POLG p.P1073L (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90). In two functional studies, authors showed that this alteration significantly reduces DNA binding affinity of the mitochondrial DNA polymerase gamma and results in increased mutability and loss of mitochondrial DNA (Baruffini E et al. Mitochondrion, 2011 Jan;11:182-90; Qian Y et al. Front Genet, 2015 Apr;6:135) This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Sep 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250419.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 4
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Complex heterozygous polymerase gamma mutation and cerebral folate deficiency in a child with refractory partial status. | Samanta D | Neurology India | 2019 | PMID: 30860128 |
The exonuclease activity of DNA polymerase γ is required for ligation during mitochondrial DNA replication. | Macao B | Nature communications | 2015 | PMID: 26095671 |
Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms. | Qian Y | Frontiers in genetics | 2015 | PMID: 25914719 |
Alpers syndrome with mutations in POLG: clinical and investigative features. | Hunter MF | Pediatric neurology | 2011 | PMID: 22000311 |
Predicting the contribution of novel POLG mutations to human disease through analysis in yeast model. | Baruffini E | Mitochondrion | 2011 | PMID: 20883824 |
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 |
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 |
Text-mined citations for rs769410130 ...
HelpRecord last updated Oct 08, 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.