ClinVar Genomic variation as it relates to human health
NM_002693.3(POLG):c.3139C>T (p.Arg1047Trp)
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(1); Likely pathogenic(9); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002693.3(POLG):c.3139C>T (p.Arg1047Trp)
Variation ID: 206548 Accession: VCV000206548.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q26.1 15: 89319065 (GRCh38) [ NCBI UCSC ] 15: 89862296 (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 Mar 8, 2017 Sep 16, 2024 May 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002693.3:c.3139C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002684.1:p.Arg1047Trp missense NM_001126131.2:c.3139C>T NP_001119603.1:p.Arg1047Trp missense NC_000015.10:g.89319065G>A NC_000015.9:g.89862296G>A NG_008218.2:g.20731C>T NG_011736.1:g.80103G>A LRG_500:g.80103G>A LRG_765:g.20731C>T LRG_765t1:c.3139C>T LRG_765p1:p.Arg1047Trp - Protein change
- R1047W
- Other names
- p.R1047W:CGG>TGG
- Canonical SPDI
- NC_000015.10:89319064: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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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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 |
221 | 2996 |
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 (6) |
criteria provided, conflicting classifications
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May 9, 2024 | RCV000188603.31 | |
Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 12, 2024 | RCV000633548.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002247605.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2022 | RCV002317146.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001808470.8 | |
not provided (1) |
no classification provided
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- | RCV003483565.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2024 | RCV003987434.1 |
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
(Aug 19, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281261.2
First in ClinVar: Aug 07, 2015 Last updated: Mar 08, 2017 |
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Uncertain significance
(Sep 20, 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: SCV000705543.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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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: SCV000887120.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
The NM_002693.2:c.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] 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.3139C>T (NP_002684.1:p.Arg1047Trp) [GRCH38: NC_000015.10:g.89319065G>A] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:18195149 . 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. 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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Likely pathogenic
(Jun 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802079.2
First in ClinVar: Aug 04, 2018 Last updated: Jun 02, 2021 |
Comment:
PS4_moderate, PM2, PM3, PM5, PP5
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 03, 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: SCV002059151.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLG related disorder (PMID:18195149, PS1_P). A different missense … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POLG related disorder (PMID:18195149, PS1_P). A different missense change at the same codon has been reported to be associated with POLG related disorder (PMID:12707443, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.848, 3CNET: 0.788, PP3_P). A missense variant is a common mechanism associated with Progressive external ophthalmoplegia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). . The variant has been reported to be in trans with a pathogenic variant as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Elevated circulating hepatic transaminase concentration (present) , Hypercholesterolemia (present) , Muscle weakness (present) , Progressive peripheral neuropathy (present) , Proximal muscle weakness in lower limbs … (more)
Elevated circulating hepatic transaminase concentration (present) , Hypercholesterolemia (present) , Muscle weakness (present) , Progressive peripheral neuropathy (present) , Proximal muscle weakness in lower limbs (present) , Psoriasiform dermatitis (present) , Stroke-like episode (present) , Abnormality of the thyroid gland (present) (less)
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Uncertain significance
(Jun 20, 2021)
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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: SCV002503548.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 3
Secondary finding: no
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Likely pathogenic
(May 04, 2022)
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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: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517373.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Progressive sclerosing poliodystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046715.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
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Likely pathogenic
(Jul 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV004229893.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with autosomal recessive POLG-related disorders. Computational tools predict that this variant is damaging. (less)
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Likely pathogenic
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Progressive sclerosing poliodystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000754794.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1047 of the POLG protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1047 of the POLG protein (p.Arg1047Trp). This variant is present in population databases (rs181860632, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 18195149, 22189570). ClinVar contains an entry for this variant (Variation ID: 206548). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Jul 27, 2022)
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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: SCV000851544.4
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The c.3139C>T (p.R1047W) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a C to T substitution … (more)
The c.3139C>T (p.R1047W) alteration is located in exon 20 (coding exon 19) of the POLG gene. This alteration results from a C to T substitution at nucleotide position 3139, causing the arginine (R) at amino acid position 1047 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Mar 12, 2024)
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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: SCV004205842.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(May 09, 2024)
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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: SCV000242226.12
First in ClinVar: Aug 07, 2015 Last updated: Sep 16, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20818383, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20818383, 31571979, 19251978, 22189570, 18195149, 29655203, 32347949, 35186329, 34690748, 37229156, 32613234, 38385069) (less)
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Uncertain significance
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803263.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: POLG c.3139C>T (p.Arg1047Trp) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the … (more)
Variant summary: POLG c.3139C>T (p.Arg1047Trp) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) 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 4e-05 in 251358 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing Mitochondrial DNA Depletion Syndrome - POLG Related (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.3139C>T has been reported in the literature in compound heterozygous individuals affected with Alpers disease (e.g. Wiltshire_2008) or progressive external ophthalmoplegia (e.g. Stewart_2009), or as a heterozygous genotype in an individual affected with mitochondrial complex I disorder without strong evidence for causality (e.g. Calvo_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20818383, 29655203, 19251978, 18195149). ClinVar contains an entry for this variant (Variation ID: 206548). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Progressive sclerosing poliodystrophy
Spinocerebellar ataxia with epilepsy Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis
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
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228843.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 11-30-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 11-30-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of eye movement (present) , Hypermetropia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Decreased response to growth hormone … (more)
Abnormality of eye movement (present) , Hypermetropia (present) , Abnormal oral cavity morphology (present) , Abnormal skull morphology (present) , Decreased response to growth hormone stimulation test (present) , Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Memory impairment (present) , Seizure (present) , Delusion (present) , Decreased fetal movement (present) , Abnormal delivery (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-11-30
Testing laboratory interpretation: Uncertain significance
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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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Novel Mutations Identified in the Chinese Han Population with Keratoconus by Next-Generation Sequencing. | Chen B | Journal of ophthalmology | 2022 | PMID: 35186329 |
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
Alpers-Huttenlocher syndrome. | Saneto RP | Pediatric neurology | 2013 | PMID: 23419467 |
Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy. | Nolte KW | Neuropathology : official journal of the Japanese Society of Neuropathology | 2013 | PMID: 22537151 |
Sensory neuronopathy in patients harbouring recessive polymerase γ mutations. | Lax NZ | Brain : a journal of neurology | 2012 | PMID: 22189570 |
Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol γ. | Euro L | Nucleic acids research | 2011 | PMID: 21824913 |
High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. | Calvo SE | Nature genetics | 2010 | PMID: 20818383 |
Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. | Kasiviswanathan R | The Journal of biological chemistry | 2009 | PMID: 19478085 |
Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. | Stewart JD | Journal of medical genetics | 2009 | PMID: 19251978 |
Juvenile Alpers disease. | Wiltshire E | Archives of neurology | 2008 | PMID: 18195149 |
Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). | Agostino A | Neurology | 2003 | PMID: 12707443 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLG | - | - | - | - |
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Text-mined citations for rs181860632 ...
HelpRecord last updated Sep 17, 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.