ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.1760C>T (p.Pro587Leu)
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.
Pathogenic(24); Likely pathogenic(10); Uncertain significance(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.1760C>T (p.Pro587Leu)
Variation ID: 13505 Accession: VCV000013505.91
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89325639 (GRCh38) [ NCBI UCSC ] 15: 89868870 (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 Apr 4, 2013 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.1760C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Pro587Leu missense NM_001126131.2:c.1760C>T NP_001119603.1:p.Pro587Leu missense NC_000015.10:g.89325639G>A NC_000015.9:g.89868870G>A NG_008218.2:g.14157C>T LRG_765:g.14157C>T LRG_765t1:c.1760C>T LRG_765p1:p.Pro587Leu P54098:p.Pro587Leu - Protein change
- P587L
- Other names
- -
- Canonical SPDI
- NC_000015.10:89325638:G:A
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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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00155
Trans-Omics for Precision Medicine (TOPMed) 0.00157
1000 Genomes Project 0.00080
Exome Aggregation Consortium (ExAC) 0.00170
1000 Genomes Project 30x 0.00062
The Genome Aggregation Database (gnomAD) 0.00160
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
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. |
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POLG | - | - |
GRCh38 GRCh37 |
1 | 2958 | |
POLGARF | - | - | GRCh38 | - | 2914 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 5, 2023 | RCV000014456.44 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2017 | RCV000020473.12 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000186576.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 24, 2019 | RCV000193529.15 | |
Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
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Nov 1, 2022 | RCV000408293.25 | |
Conflicting interpretations of pathogenicity (15) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000427845.53 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 15, 2014 | RCV000415307.10 | |
Pathogenic (2) |
no assertion criteria provided
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Apr 7, 2017 | RCV000508752.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 15, 2022 | RCV001004602.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2021 | RCV001610290.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2021 | RCV001642226.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813986.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 8, 2021 | RCV002227034.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2021 | RCV001847603.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2018 | RCV002313709.8 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2022 | RCV001813743.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 19, 2022 | RCV002319424.8 | |
not provided (1) |
no classification provided
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- | RCV003458332.1 | |
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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. |
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Pathogenic
(Jul 15, 2014)
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criteria provided, single submitter
Method: clinical testing
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Global developmental delay
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492823.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Aug 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511317.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Dec 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial neurogastrointestinal encephalomyopathy
Affected status: unknown
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746435.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Age: 20-29 years
Sex: female
Geographic origin: Iran
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Pathogenic
(Oct 05, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331603.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 21
Sex: mixed
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Uncertain significance
(May 28, 2019)
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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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Mendelics
Accession: SCV001139681.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Nov 08, 2017)
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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
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680342.2
First in ClinVar: Feb 08, 2018 Last updated: Dec 15, 2018 |
Observation 1:
Sex: female
Tissue: blood
Observation 2:
Sex: female
Tissue: blood
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Pathogenic
(Jul 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248555.2
First in ClinVar: Oct 05, 2015 Last updated: Jun 12, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446808.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) , … (more)
Microcephaly (present) , Hypotonia (present) , Flexion contracture (present) , Respiratory insufficiency (present) , Developmental regression (present) , Myopathy (present) , Muscular dystrophy (present) , Cardiorespiratory arrest (present) , Developmental stagnation (present) (less)
Sex: male
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Pathogenic
(Feb 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tip-toe gait
Affected status: yes
Allele origin:
maternal
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Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino
Accession: SCV001832553.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Comment:
c.1760C>T p.(Pro587Leu) [dbSNP: rs113994096, Frequenz: A=0.15%, GnomAD] is rated by the majority (15 entries) as "probably pathogenic" and "pathogenic" in the ClinVar mutation database.
Clinical Features:
Pes cavus (present)
Age: 10-19 years
Sex: male
Method: Gene panel analysis
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Likely pathogenic
(Nov 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105557.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Likely pathogenic
(Mar 28, 2022)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503521.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 11
Secondary finding: no
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Uncertain significance
(Dec 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Stroke disorder
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506434.1
First in ClinVar: May 07, 2022 Last updated: May 07, 2022 |
Comment:
ACMG categories: PM1,PM2,PP3,BP1
Number of individuals with the variant: 1
Clinical Features:
Stroke disorder (present)
Age: 30-39 years
Sex: male
Tissue: blood
|
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Likely pathogenic
(Sep 01, 2022)
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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
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572626.1
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: 0.154%). Missense changes are a common disease-causing mechanism. … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.154%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013505). The variant was observed in cis with NM_002693.3:c.752C>T (p.Thr251Ile) in many individuals affected with POLG-related diseases (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal pulmonary interstitial morphology (present)
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Pathogenic
(Oct 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
paternal
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Genetic Medico-Diagnostic Laboratory Genica
Accession: SCV002605540.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was found with an allele frequency of 0.1540% (one reported homozygote) … (more)
The variant was classified as pathogenic according to the ACMG Guidelines, 2015. The variant was found with an allele frequency of 0.1540% (one reported homozygote) in the control populations from the gnomAD v2.1.1 project. In silico analysis by Polyphen-2, SIFT and Mutation-Taster predicted it as damaging. The amino acid change is in a highly conserved position and proline and leucine have moderate physicochemical difference. The variant was identified in cis with variant POLG(NM_002693.3):c.752C>T in a patient with Hypertrophic cardiomyopathy. The patient is also carrier of variants GTPBP3(NM_032620.4):c.181G>C and GTPBP3(NM_032620.4):c.1199C>T in compound heterozygous state. (less)
Comment on evidence:
The variant was first identified through whole exome sequencing and later confirmed in the proband in heterozygous state by Sanger sequencing. The patient's healthy half-brother … (more)
The variant was first identified through whole exome sequencing and later confirmed in the proband in heterozygous state by Sanger sequencing. The patient's healthy half-brother is a carrier of the variant as determined by Sanger sequencing. (less)
Segregation observed: no
Secondary finding: no
Method: Whole Exome Sequencing
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Pathogenic
(Nov 30, 2018)
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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: SCV000847670.3
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.P587L pathogenic mutation (also known as c.1760C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at … (more)
The p.P587L pathogenic mutation (also known as c.1760C>T), located in coding exon 9 of the POLG gene, results from a C to T substitution at nucleotide position 1760. The proline at codon 587 is replaced by leucine, an amino acid with similar properties. This mutation has been reported to occur almost exclusively in cis with p.T251I (c.752C>T) and this syntenic mutation combination accounts for approximately 6% of all disease causing alleles in POLG (Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). This syntenic mutation combination has been detected alone, in trans with various other POLG mutations and alterations, and as homozygous, in individuals with Alpers syndrome, autosomal recessive external ophthalmoplegia (arPEO), neuropathy, myopathy, MNGIE, intellectual disability and various other POLG-deficiency symptoms (Van Goethem G et al. Eur. J. Hum. Genet., 2003 Jul;11:547-9; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Uusimaa J et al. Epilepsia, 2013 Jun;54:1002-11; Weiss MD et al. Muscle Nerve, 2010 Jun;41:882-5; Horvath R et al. Brain, 2006 Jul;129:1674-84; Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). Of note, this mutation has been detected without p.T251I in conjunction with the p.R853W alteration (phase was not confirmed) in an individual with PEO, ptosis, and multiple mtDNA deletions (González-Vioque E et al. Arch. Neurol., 2006 Jan;63:107-11). In addition, biochemical characterization of P587L mutant revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; T251I+P587L double mutant showed synergistic effect and had more severe dysfunction than P587L alone (DeBalsi KL et al. J. Biol. Chem., 2017 03;292:4198-4209). Based on the supporting evidence, p.P587L is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
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Likely pathogenic
(Apr 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4b
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556643.3
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2023 |
Comment:
The POLG c.1760C>T variant is classified as LIKELY PATHOGENIC (PS3, PS4_moderate, PP1_moderate, PP3) This sequence change in exon 10 of 23 replaces proline with leucine … (more)
The POLG c.1760C>T variant is classified as LIKELY PATHOGENIC (PS3, PS4_moderate, PP1_moderate, PP3) This sequence change in exon 10 of 23 replaces proline with leucine at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (gnomAD 232/152196 heterozygotes, 0 homozygote). The variant has been reported in dbSNP (rs113994096). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 13505). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in many individuals affected with POLG-related diseases, and in almost all cases it has been observed on the same chromosome (in cis) with the second (p.Thr251Ile) variant also detected in this patient (PMID: 25660390, 14635118, 15349879, 16621917, 19189930, 21880868) (PS4_moderate). In many of these previously reported cases, the two variants in cis were observed on the opposite chromosome (in trans) from a third, pathogenic variant in an affected individual. The p.Pro587Leu and p.Thr251Ile variant combination in cis accounts for approximately 6% of disease-causing alleles in POLG-related disorders, mainly in Caucasians (PMID: 21880868). The p.Pro587Leu and Thr251Ile variants in cis have been reported to segregate with disease in several families (PMID: 12210792, 15349879) (PP1_moderate). Functional studies of the Thr251Ile and Pro587Leu variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity and compromised DNA processivity; the Thr251Ile+Pro587Leu double variant showed a synergistic effect and had more severe dysfunction than the either of the variants alone (PMID: 28154168) (PS3). NO THIRD POLG variant was detected in this patient (less)
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Pathogenic
(Jul 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003818479.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-related disorder
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801567.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The POLG c.1760C>T p.(Pro587Leu) missense variant is well described in the literature and has been reported in individuals with a phenotype consistent with POLG-related spectrum … (more)
The POLG c.1760C>T p.(Pro587Leu) missense variant is well described in the literature and has been reported in individuals with a phenotype consistent with POLG-related spectrum disorders (Van Goethem et al., 2003; Filosto et al. 2003; Lamantea et al. 2004; Wong et al., 2008; Ashley et al., 2008; Burusnukul et al. 2009; Weiss et al. 2010; Tang et al. 2011; Horvath et al., 2006; Dames et al. 2013; Helbling et al. 2013; Uusimaa et al. 2013). In almost all of the reported cases, the p.Pro587Leu variant was found in cis with p.Thr251Ile as the complex allele [p.Thr251Ile; p.Pro587Leu]. In an additional two individuals, the p.Pro587Leu variant was found as part of a complex allele with a p.Pro589Leu variant. The p.Pro587Leu variant has also been reported independently in three individuals from the same family in a heterozygous state displaying a dominant pattern of inheritance. Euro et al. (2011) assessed the structure-function relationships of variants in the POLG gene and reported that the p.Pro587Leu variant constrains the Beta-hairpin loop between the IP and AID subdomains and postulate it likely reduces processivity as a result of misalignment of the ptDNA with respect to the catalytic site. DeBalsi et al. (2017) investigated the biochemical properties of purified recombinant Pol gamma p.Pro587Leu protein expressed using the baculovirus Sf9 system. Experiments demonstrated that the p.Pro587Leu variant caused a two-fold reduction in DNA binding affinity and significantly reduced thermostability. The catalytic efficiency of the p.Pro587Leu protein was reduced to approximately 32% of the wildtype level. The [p.Thr251Ile; p.Pro587Leu] variant protein demonstrated a more severe catalytic dysfunction, retaining 5% activity compared to the wild type protein and suggesting that these two variants have a synergistic effect. Based on the collective evidence the p.Pro587Leu variant is classified as pathogenic when found as part of a complex allele and of uncertain significance when found independently. (less)
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001149568.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Comment:
POLG: PM3:Very Strong, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 23
|
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Likely pathogenic
(Apr 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884404.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
|
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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: SCV000886904.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
The NM_002693.2:c.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] 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.1760C>T (NP_002684.1:p.Pro587Leu) [GRCH38: NC_000015.10:g.89325639G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15349879 ; 12825077 . 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Mitochondrial DNA depletion syndrome 4b
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163772.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
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Likely pathogenic
(Jan 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial dna depletion syndrome 4a (alpers type)
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448887.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Muscular hypotonia (present) , Laryngomalacia (present) , Autistic disorder of childhood onset (present) , Global developmental delay (present) , Hernia (present) , Generalized hypotonia (present) … (more)
Muscular hypotonia (present) , Laryngomalacia (present) , Autistic disorder of childhood onset (present) , Global developmental delay (present) , Hernia (present) , Generalized hypotonia (present) , Autistic behavior (present) , Failure to thrive (present) , Abnormal facial shape (present) , Esotropia (present) , Oligohydramnios (present) , Growth delay (present) , Strabismus (present) , Cryptorchidism (present) , Abnormality of the atrial septum (present) , Dysphagia (present) , Retrognathia (present) , Infantile muscular hypotonia (present) (less)
Sex: male
|
|
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: SCV001519175.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
Pathogenic
(Jun 28, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Accession: SCV001529893.1
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]. These two variants have been previously reported as pathogenic and are frequently … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. These two variants have been previously reported as pathogenic and are frequently in cis configuration [PMID 12210792, 19189930, 23665194, 28154168, 22616202, 25585994, 23783014, 26468652, 19566497, 20513108, 24122062] (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760353.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755620.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
Uncertain significance
(Jul 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4b
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950111.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015)
|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-related disorder
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061213.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; … (more)
The c.1760C>T;p.(Pro587Leu) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13505; OMIM 174763.0011; PMID: 12825077; 25660390; 12975295; 1539879; 19578034; 24265579; 23448099;25742477; 26224072) - PS4.The p.(Pro587Leu) was detected in trans with a pathogenic variant (PMID: 19578034) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 25660390) - BP2. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 4
Sex: mixed
Geographic origin: Brazil
|
|
Pathogenic
(Feb 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Mitochondrial DNA depletion syndrome 4b
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512294.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PS4, PM3 strong, PP3 supporting
Geographic origin: Brazil
|
|
Pathogenic
(Jun 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-related disorder
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002568173.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
Comment:
PS3, PM3_Strong, PP1, PP3
|
|
Pathogenic
(Jul 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581640.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 10
Sex: female
|
|
Pathogenic
(Jul 27, 2021)
|
criteria provided, single submitter
Method: research
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Affected status: unknown
Allele origin:
unknown
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: CSER_NCGENES_2
Accession: SCV002587017.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Thin upper lip vermilion (present) , Bulbous nose (present) , Upslanted palpebral fissure (present) , Decreased response to growth hormone stimulation test (present) , Specific … (more)
Thin upper lip vermilion (present) , Bulbous nose (present) , Upslanted palpebral fissure (present) , Decreased response to growth hormone stimulation test (present) , Specific learning disability (present) , Obesity (present) (less)
|
|
Uncertain significance
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000543885.9
First in ClinVar: Dec 06, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 587 of the POLG protein (p.Pro587Leu). This variant is present in population databases (rs113994096, gnomAD 0.3%), 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 conditions, and in almost all cases it was observed on the same chromosome (in cis) with a second (p.Thr251Ile) variant (PMID: 12210792, 14635118, 15349879, 16621917, 19189930, 21880868, 25660390). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. To date, the p.Pro587Leu variant has not been observed independent from the p.Thr251Ile variant in individuals with autosomal recessive POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 13505). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 28154168). In summary, this is a rare variant that is almost always observed in cis with a second variant. It has been shown to segregate with disease, and has also been observed in many individuals with sporadic disease. However, because it almost always occurs in cis with p.Thr251Ile, the individual contribution of this variant to disease cannot be disambiguated. For these reasons, this change has been classified as a Variant of Uncertain Significance. (less)
|
|
Likely pathogenic
(Dec 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POLG-related disorder
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003804668.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
_x000D_Criteria applied: PS3, PS4_SUP, PP3, PP1
|
|
Likely pathogenic
(Feb 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome 4b
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV003843876.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
A heterozygous missense variation in exon 10 of the POLG gene that results in the amino acid substitution of Leucine for Proline at codon587 was … (more)
A heterozygous missense variation in exon 10 of the POLG gene that results in the amino acid substitution of Leucine for Proline at codon587 was detected. The observed variant c.1760C>T (p.Pro587Leu) has a minor allele frequancy of 0.08% and 0.1% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Sensorineural hearing loss disorder (present) , Hypotonia (present) , Elevated circulating creatine kinase concentration (present)
Age: 20-29 years
Sex: male
Comment on evidence:
DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence … (more)
DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication (less)
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
Likely pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011121.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Uncertain significance
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802089.3
First in ClinVar: Aug 04, 2018 Last updated: Jan 26, 2024 |
Comment:
PP3, PM2, PS3_moderate
Number of individuals with the variant: 11
|
|
Pathogenic
(Apr 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics Inc
Accession: SCV000614707.4
First in ClinVar: Oct 05, 2015 Last updated: Jan 26, 2024 |
Comment:
This variant is seen in cis with POLG c.752C>T (p.Thr251Ile), and the pathogenicity assessment is based on data for NM_002693.2:c.752C>T(;)1760C>T.
|
|
Pathogenic
(Sep 01, 2004)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 4B (MNGIE TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034706.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 27, 2016 |
Comment on evidence:
For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion … (more)
For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662) by Van Goethem et al. (2003), see 174763.0007. Filosto et al. (2003) identified the P587L mutation in 2 sibs with PEO, exercise intolerance, distal limb weakness, and peripheral neuropathy. One of the sibs also had abdominal cramping and gastrointestinal dysmotility suggesting MNGIE syndrome (603041). An unrelated patient with the P587L mutation had progressive hearing loss, ataxia, PEO, distal myopathy, and hypogonadism. Lamantea and Zeviani (2004) identified the P587L mutation and the T251I mutation (174763.0007) on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG mutation in trans with the 2 cis alleles. (less)
|
|
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: SCV000575915.1
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Number of individuals with the variant: 1
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807948.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
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: SCV001971389.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Pathogenic
(Sep 01, 2004)
|
no assertion criteria provided
Method: literature only
|
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000240152.2
First in ClinVar: Jul 31, 2015 Last updated: Mar 27, 2016 |
Comment on evidence:
For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion … (more)
For discussion of the pro587-to-leu (P587L) mutation in the POLG gene that was found in compound heterozygous state in 2 sisters with mitochondrial DNA depletion syndrome-4B (MTDPS4B; 613662) by Van Goethem et al. (2003), see 174763.0007. Filosto et al. (2003) identified the P587L mutation in 2 sibs with PEO, exercise intolerance, distal limb weakness, and peripheral neuropathy. One of the sibs also had abdominal cramping and gastrointestinal dysmotility suggesting MNGIE syndrome (603041). An unrelated patient with the P587L mutation had progressive hearing loss, ataxia, PEO, distal myopathy, and hypogonadism. Lamantea and Zeviani (2004) identified the P587L mutation and the T251I mutation (174763.0007) on the same allele in 3 families with autosomal recessive PEO (PEOB1; 258450); each of the families was compound heterozygous for another POLG mutation in trans with the 2 cis alleles. (less)
|
|
Pathogenic
(Dec 12, 2016)
|
no assertion criteria provided
Method: research
|
Progressive sclerosing poliodystrophy
Affected status: yes
Allele origin:
maternal
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536728.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
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: SCV001740685.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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: SCV001926715.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Likely 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: SCV001952060.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 25, 2021 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Mitochondrial disease
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040907.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Mitochondrial DNA depletion syndrome 4b
Progressive sclerosing poliodystrophy Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown,
paternal
|
GenomeConnect - Brain Gene Registry
Accession: SCV004176863.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
Variant classified as Pathogenic and reported on 04-20-2016 by Children's National Medical Center. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic … (more)
Variant classified as Pathogenic and reported on 04-20-2016 by Children's National Medical Center. This variant was identified in multiple related participants enrolled in GenomeConnect. Phenotypic data from the proband has been submitted with this variant. Additional phenotypic information for family members might be available from GenomeConnect. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne?from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Observation 1:
Clinical Features:
Family history (present)
Indication for testing: Family Testing
Age: 40-49 years
Sex: male
Method: Familial/Targeted Variant Analysis
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-06-02
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Delayed speech and language development (present) , Atonic seizure (present) , EEG abnormality (present) , Drooling (present) , Cerebellar ataxia (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Children's National Medical Center
Date variant was reported to submitter: 2016-04-20
Testing laboratory interpretation: Pathogenic
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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 |
---|---|---|---|---|
POLG-Related Disorders. | Adam MP | - | 2024 | PMID: 20301791 |
Neuropathic Pain as Main Manifestation of POLG-Related Disease: A Case Report. | Lang-Orsini M | Frontiers in neurology | 2022 | PMID: 35350396 |
Forecasting stroke-like episodes and outcomes in mitochondrial disease. | Ng YS | Brain : a journal of neurology | 2022 | PMID: 34927673 |
Polymerase Gamma Mitochondrial DNA Depletion Syndrome Initially Presenting as Disproportionate Respiratory Distress in a Moderately Premature Neonate: A Case Report. | Franklin AD | Frontiers in genetics | 2021 | PMID: 34194468 |
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion. | Silva-Pinheiro P | Nucleic acids research | 2021 | PMID: 33956154 |
Functional analysis of a novel POLγA mutation associated with a severe perinatal mitochondrial encephalomyopathy. | Darin N | Neuromuscular disorders : NMD | 2021 | PMID: 33579567 |
Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis. | Wiedemann A | Journal of human genetics | 2020 | PMID: 31645654 |
Late-onset presentation of POLG1-associated mitochondrial disease. | Meira B | BMJ case reports | 2019 | PMID: 30936349 |
The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort. | Piekutowska-Abramczuk D | Mitochondrion | 2019 | PMID: 30423451 |
Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations. | Masingue M | Mitochondrion | 2019 | PMID: 29474836 |
High-frequency actionable pathogenic exome variants in an average-risk cohort. | Rego S | Cold Spring Harbor molecular case studies | 2018 | PMID: 30487145 |
Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. | Theunissen TEJ | Frontiers in genetics | 2018 | PMID: 30369941 |
Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants. | Castiglioni C | European journal of human genetics : EJHG | 2018 | PMID: 29358615 |
Decreased male reproductive success in association with mitochondrial dysfunction. | Martikainen MH | European journal of human genetics : EJHG | 2017 | PMID: 28812649 |
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 |
Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations. | DeBalsi KL | The Journal of biological chemistry | 2017 | PMID: 28154168 |
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 |
The wide POLG-related spectrum: An integrated view. | Béreau M | Journal of the neurological sciences | 2016 | PMID: 27538604 |
Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease. | Chrysostomou A | Neuropathology and applied neurobiology | 2016 | PMID: 26337858 |
The spectrum of epilepsy caused by POLG mutations. | Janssen W | Acta neurologica Belgica | 2016 | PMID: 26104464 |
Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties. | Singh B | PloS one | 2015 | PMID: 26468652 |
Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. | Wahbi K | European heart journal | 2015 | PMID: 26224072 |
Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes. | Komulainen T | JIMD reports | 2015 | PMID: 25940035 |
Mitochondrial dysfunction and risk of cancer. | Lund M | British journal of cancer | 2015 | PMID: 25742477 |
The in cis T251I and P587L POLG1 base changes: description of a new family and literature review. | Scuderi C | Neuromuscular disorders : NMD | 2015 | PMID: 25660390 |
Evidence for polymerase gamma, POLG1 variation in reduced mitochondrial DNA copy number in Parkinson's disease. | Gui YX | Parkinsonism & related disorders | 2015 | PMID: 25585994 |
Variations of mitochondrial DNA polymerase γ in patients with Parkinson's disease. | Ylönen S | Journal of neurology | 2013 | PMID: 24122062 |
The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. | Reeve A | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2013 | PMID: 23804100 |
Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure. | Helbling D | Journal of pediatric gastroenterology and nutrition | 2013 | PMID: 23783014 |
The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders. | Dames S | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23665194 |
Prospective study of POLG mutations presenting in children with intractable epilepsy: prevalence and clinical features. | Uusimaa J | Epilepsia | 2013 | PMID: 23448099 |
POLG1 mutations and stroke like episodes: a distinct clinical entity rather than an atypical MELAS syndrome. | Cheldi A | BMC neurology | 2013 | PMID: 23324391 |
A novel POLG gene mutation in a patient with SANDO. | Kurt B | Journal of experimental and integrative medicine | 2012 | PMID: 24265579 |
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 |
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts. | Stewart JD | Biochimica et biophysica acta | 2011 | PMID: 21138766 |
Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) in late life due to compound heterozygous POLG mutations. | Weiss MD | Muscle & nerve | 2010 | PMID: 20513108 |
Is it ADEM, POLG, or both? | Harris MO | Archives of neurology | 2010 | PMID: 20385918 |
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 |
Phenotypic variations in 3 children with POLG1 mutations. | Burusnukul P | Journal of child neurology | 2009 | PMID: 19189930 |
Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. | Taanman JW | Human mutation | 2009 | PMID: 18828154 |
Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family. | Houinato D | Neuromuscular disorders : NMD | 2007 | PMID: 17418573 |
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 |
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 |
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. | Ferrari G | Brain : a journal of neurology | 2005 | PMID: 15689359 |
Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene. | Lamantea E | Annals of neurology | 2004 | PMID: 15349879 |
POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. | Di Fonzo A | Human mutation | 2003 | PMID: 14635118 |
Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. | Filosto M | Archives of neurology | 2003 | PMID: 12975295 |
Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. | Van Goethem G | European journal of human genetics : EJHG | 2003 | PMID: 12825077 |
Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). | Agostino A | Neurology | 2003 | PMID: 12707443 |
Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. | Lamantea E | Annals of neurology | 2002 | PMID: 12210792 |
Muscle weakness in a Japanese family of Arg1239His mutation hypokalemic periodic paralysis. | Kusumi M | Psychiatry and clinical neurosciences | 2001 | PMID: 11555352 |
Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families. | Elbaz A | American journal of human genetics | 1995 | PMID: 7847370 |
Ready-mix charcoal/sorbitol. | Jessen LM | Annals of emergency medicine | 1992 | PMID: 1539879 |
http://tools.niehs.nih.gov/polg/ | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs113994096 ...
HelpRecord last updated Apr 20, 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.