ClinVar Genomic variation as it relates to human health
NM_000113.3(TOR1A):c.904GAG[1] (p.Glu303del)
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_000113.3(TOR1A):c.904GAG[1] (p.Glu303del)
Variation ID: 5180 Accession: VCV000005180.61
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 9q34.11 9: 129814062-129814064 (GRCh38) [ NCBI UCSC ] 9: 132576341-132576343 (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 Aug 4, 2024 Feb 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000113.3:c.904GAG[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000104.1:p.Glu303del inframe deletion NM_000113.3:c.907_909del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000113.2:c.904_906delGAG NP_000104.1:p.Glu303del NM_000113.2:c.907_909delGAG NC_000009.12:g.129814062CTC[1] NC_000009.11:g.132576341CTC[1] NG_008049.1:g.15096GAG[1] LRG_1029:g.15096GAG[1] LRG_1029t1:c.904GAG[1] LRG_1029p1:p.Glu303del - Protein change
- E303del
- Other names
- E302delE
- Canonical SPDI
- NC_000009.12:129814061:CTCCTC:CTC
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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.
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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
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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TOR1A | - | - |
GRCh38 GRCh37 |
185 | 248 |
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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Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Feb 29, 2024 | RCV000005488.31 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000412981.42 | |
Pathogenic (2) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000584141.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV001266579.11 | |
TOR1A-related disorder
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2023 | RCV003335014.2 |
Pathogenic (1) |
criteria provided, single submitter
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Oct 15, 2021 | RCV002504750.8 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2014 | RCV004558237.1 |
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
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
Affected status: yes
Allele origin:
maternal
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3billion
Accession: SCV002011944.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
Same infarme deletion variane has been previously reported as de novoo in similarly affected unrelated individual (PMID: 11973627, 9618171, and 10225357). Functional studies provide strong … (more)
Same infarme deletion variane has been previously reported as de novoo in similarly affected unrelated individual (PMID: 11973627, 9618171, and 10225357). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24930953). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000106, PM2). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Dystonic disorder (present) , Spasticity (present) , Focal dystonia (present)
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Pathogenic
(Jun 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline,
maternal,
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150297.3
First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Generalized dystonia (present) , Dystonic disorder (present) , Arm dystonia (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Tremor (present) , Dystonic disorder (present)
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Limb dystonia (present) , Limb tremor (present)
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
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Pathogenic
(Sep 19, 2022)
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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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Revvity Omics, Revvity
Accession: SCV002022386.2
First in ClinVar: Nov 29, 2021 Last updated: Mar 11, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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TOR1A-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046095.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
The c.907_909del variant leads to the deletion of one amino acid residue in the TOR1A protein (p.Glu303del) but preserves the reading frame. The c.907_909delGAG variant … (more)
The c.907_909del variant leads to the deletion of one amino acid residue in the TOR1A protein (p.Glu303del) but preserves the reading frame. The c.907_909delGAG variant is the most common pathogenic variant associated with TOR1A-related primary dystonia (PMID: 9288096). It has been previously reported both as an inherited heterozygous variant in familial cases and a de novo heterozygous variant in several individuals with early-onset dystonia (PMID: 22976004, 22226333, 25403864, 22770546, 9288096, 9874484, 11973627, 12481989, 24930953, 24931141). It has also been reported in the homozygous state or as a compound heterozygote with another TOR1A variant in several individuals with arthrogryposis (PMID: 28516161, 29053766 ). Functional studies indicate that this variant causes misfolding of the protein and results in its abnormal cellular localization and aggregation (PMID: 8940237, 24930953, 19651773, 24951854, 19339278). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.01% (30/282878) and thus is presumed to be rare. Analysis of the maternal sample showed that the mother is heterozygous for this variant. Based on the available evidence, the c.907_909del (p.Glu303del) variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101509.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The in frame deletion in TOR1A c.907_909del (p.Glu303del) variant has been reported in heterozygous state in multiple patients affected with early onset primary dystonia (Vulinovic … (more)
The in frame deletion in TOR1A c.907_909del (p.Glu303del) variant has been reported in heterozygous state in multiple patients affected with early onset primary dystonia (Vulinovic F et al., 2014). Functional studies demonstrate that c.907_909delGAG results in abnormal cellular localization and aggregation of the misfolded protein (Gordon et al., 2008; Hettich et al., 2014). This variant has allele frequency of 0. 01061% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic/Likely pathogenic. This p.Glu303del causes deletion of amino acid Glutamic Acid at position 303. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Dystonic disorder (present) , Choreoathetosis (present)
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Pathogenic
(Jun 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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TOR1A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116561.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TOR1A c.907_909delGAG variant is predicted to result in an in-frame deletion (p.Glu303del). This variant is well documented as causative for autosomal dominant torsion dystonia … (more)
The TOR1A c.907_909delGAG variant is predicted to result in an in-frame deletion (p.Glu303del). This variant is well documented as causative for autosomal dominant torsion dystonia type one (DYT1), and functional studies support its pathogenicity (Gordon and Gonzalez-Alegre. 2008. PubMed ID: 18940237; Hettich et al. 2014. PubMed ID: 24930953; Ozelius et al. 1997. PubMed ID: 9288096). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-132576340-TCTC-T) and has been interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/5180/) .Variable expressivity and incomplete penetrance are documented for this variant (Ozelius et al. 1993. PubMed ID: 20301665). This variant is classified as pathogenic. (less)
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dystonic disorder
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000283510.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This variant, c.907_909del, results in the deletion of 1 amino acid(s) of the TOR1A protein (p.Glu303del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.907_909del, results in the deletion of 1 amino acid(s) of the TOR1A protein (p.Glu303del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs724159981, gnomAD 0.2%). This variant has been observed in individual(s) with early onset primary dystonia (PMID: 9288096, 9874484, 11973627, 12481989, 20301665, 24930953, 24931141). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5180). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TOR1A function (PMID: 18940237, 19339278, 19651773, 24930953, 24931141). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801528.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The TOR1A c.907_909delGAG (p.Glu303del) variant results in an in-frame deletion of glutamic acid at amino acid position 303. This variant is the most common variant … (more)
The TOR1A c.907_909delGAG (p.Glu303del) variant results in an in-frame deletion of glutamic acid at amino acid position 303. This variant is the most common variant found in individuals with early-onset primary dystonia (Ozelius et al. 1997; Ozelius et al. 2016). Across a selection of the available literature, the p.Glu303del variant has been identified in at least 80 individuals with early-onset dystonia, including at least 78 individuals in a heterozygous state and two in a homozygous state (Ozelius et al. 1997; Klein et al. 1998; Hjermind et al. 2002; Saunders-Pullman et al. 2014; Reichert et al. 2017; Kariminejad et al. 2017; Ma et al. 2018). Of these, the variant occurred in a de novo state in at least three individuals (Klein et al. 1998; Hjermind et al. 2002). The highest frequency of this allele in the Genome Aggregation Database is 0.001729 in the Ashkenazi Jewish population (version 3.1.2). This frequency is high but is consistent with reduced penetrance, estimated at 30 to 40 percent, and with the p.Glu303del variant noted to be a founder variant (Ozelius et al. 1997; Ozelius et al. 2016). In vitro analysis of the p.Glu303del variant in BHK21 cells, neurons, and patient fibroblasts demonstrated altered cellular localization and formation of spheroid bodies in the nuclear envelope (Goodchild et al. 2008). Overexpression of the p.Glu303del variant in mice demonstrated significant recapitulation of phenotypes, behaviors, age of onset, and biochemical alterations that are found in affected individuals (Shashidharan et al. 2005). Based on the available evidence, the c.907_909delGAG (p.Glu303del) variant is classified as pathogenic for early onset primary dystonia. (less)
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Pathogenic
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248848.24
First in ClinVar: May 09, 2020 Last updated: Aug 04, 2024 |
Comment:
TOR1A: PM6:Strong, PP1:Strong, PM4:Supporting, PS3:Supporting
Number of individuals with the variant: 13
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Likely pathogenic
(May 10, 2018)
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criteria provided, single submitter
Method: research
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Early-onset generalized limb-onset dystonia
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000778594.1 First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 21, 2018)
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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: SCV000854896.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dystonia-1, torsion
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434932.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.907_909del (p.Glu303del) variant has been detected in 10 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/9-132576340-TCTC-T) and leads to the deletion of a glutamine … (more)
This c.907_909del (p.Glu303del) variant has been detected in 10 heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/9-132576340-TCTC-T) and leads to the deletion of a glutamine at amino acid position 303 of the TOR1A protein. This c.907_909del (p.Glu303del) variant has been reported in multiple patients with dystonia [PMID 9288096, 22976004, 22226333, 25403864, 22770546]. Functional assays and in vivo animal models demonstrated that this deletion affect the function of the protein [ PMID 18940237, 24930953, 19651773, 24951854, 19339278]. This variant is thus classified as pathogenic. (less)
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Pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762213.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Clinical Features:
Dystonic disorder (present) , Generalized dystonia (present)
Sex: male
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Pathogenic
(Jun 09, 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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GeneDx
Accession: SCV000491317.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
Observed with a TOR1A variant on the opposite allele (in trans) in a patient with arthrogryposis in published literature (Reichert et al., 2017); Published functional … (more)
Observed with a TOR1A variant on the opposite allele (in trans) in a patient with arthrogryposis in published literature (Reichert et al., 2017); Published functional studies demonstrate that c.907_909delGAG results in abnormal cellular localization and aggregation of the misfolded protein (Gordon et al., 2008; Hettich et al., 2014); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31447099, 32243914, 31130284, 28432771, 29111010, 29801903, 31737037, 31347572, 29188619, 28102337, 27490483, 28516161, 29053766, 11973627, 24500857, 16773641, 27666935, 18519876, 22976004, 22770546, 22226333, 19651773, 26183317, 24951854, 25403864, 27123488, 9288096, 18940237, 19339278, 24931141, 24930953, 27939583) (less)
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Pathogenic
(Aug 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581776.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Oct 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
Arthrogryposis multiplex congenita 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002815146.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 17, 2023)
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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: SCV001444755.3
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.907_909delGAG (p.E303del) alteration, located in coding exon 5 of the TOR1A gene, results from an in-frame GAG deletion at nucleotide positions 907 to 909. … (more)
The c.907_909delGAG (p.E303del) alteration, located in coding exon 5 of the TOR1A gene, results from an in-frame GAG deletion at nucleotide positions 907 to 909. This results in the in-frame deletion of a glutamic acid residue at codon 303. Based on data from gnomAD, the variant has an overall frequency of 0.011% (30/282878) total alleles studied. The highest observed frequency was 0.154% (16/10370) of Ashkenazi Jewish alleles. This alteration is the most common pathogenic variant known to cause early onset generalized dystonia, accounting for approximately 70% of patients (reviewed in Grundmann, 2003). Rarely, patients heterozygous for this alteration present with other forms of dystonia with variable progression (Grundmann, 2003; Wong, 2005). Variability within the same family has been described and disease penetrance is estimated to be 30-40% (Ozelius, 1993; Ozelius, 1997; Grundmann, 2003). In addition, this alteration was reported in the homozygous state two unrelated Iranian individuals with congenital arthrogryposis, tremor, strabismus, and variable developmental delay/intellectual disability (Kariminejad, 2017). This amino acid position is well conserved in available vertebrate species. Functional and structural studies demonstrate that this variant results in weakened and defective protein function (Zhao, 2013; Demircioglu, 2016). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Early-onset generalized limb-onset dystonia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001530110.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 09, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951695.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Sep 01, 2014)
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no assertion criteria provided
Method: literature only
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DYSTONIA 1, TORSION, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025670.5
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting … (more)
Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting in the loss of 1 of a pair of conserved glutamic acid residues in a novel ATP-binding protein termed torsin-A. The GAG deletion was the only mutation detected in a large number of patients from different ethnic backgrounds. Most (90%) patients with an atypical presentation had no identifiable mutation in the DYT1 gene. At least 4 different background haplotypes were observed with the GAG deletion, indicating that the mutation had arisen more than once to cause ITD. Given the highly variable phenotype and reduced penetrance observed in ITD, the identification of the DYT1 mutation was a major advance for accurate diagnosis of the disorder. Because this mutation deletes one of 2 contiguous glutamic acid codons of the DYT1 gene, Goodchild and Dauer (2004) and Naismith et al. (2004) referred to it as delE302/303. Ikeuchi et al. (1999) described the apparently sporadic occurrence of primary torsion dystonia in a 25-year-old Japanese man who first noted at age 13 years that his left shoulder occasionally turned involuntarily to the left. By age 16 years his neck also became involved, twisting involuntarily to the left like his shoulder. He showed moderate improvement with diazepam (20 mg) and trihexyphenidyl (18 mg). Neither parent and none of the 4 grandparents showed any movement disorder or complained of writer's cramp. Nucleotide sequence analysis detected the GAG deletion in the patient's DYT1 gene. Restriction fragment length polymorphism (RFLP) analysis using BseRI showed that the GAG deletion was present not only in the patient but also in his mother, but not in his father. Kamm et al. (1999) examined 57 patients with idiopathic torsion dystonia for the 3-bp GAG deletion in the DYT1 gene. Three of 5 patients with early limb-onset torsion dystonia, one of them with a positive family history, tested positive for the mutation, as did 1 young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as 5 other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggested that the GAG deletion is responsible for most cases of typical early limb-onset dystonia, but not for other types of dystonia, in the German population studied. Hjermind et al. (2002) performed mutation analysis for the GAG deletion in the DYT1 gene in 107 unrelated Danish probands with primary torsion dystonia (37 were known familial cases). Clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion was only detected in 3 (2.8%) in whom the phenotype was typical. This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation. Ikeuchi et al. (2002) studied 6 unrelated Japanese pedigrees with dystonia due to the GAG deletion in the DYT1 gene. None of the haplotypes in these families shared strong similarity to the Ashkenazi Jewish haplotype, suggesting that the GAG deletion occurred independently in the Japanese population. Some sharing was observed among haplotypes of the Japanese families, but there was nonetheless an indication of multiple independent events resulting in the deletion in these pedigrees. Among 256 patients with various subtypes of dystonia, Grundmann et al. (2003) identified 6 patients (2%) with the GAG deletion in the DYT1 gene. Two patients had classic features of early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with involvement of cranial and cervical muscles), and 2 had only writer's cramp with slight progression. Apart from 1 patient with onset at 41 years, the mean age at onset was 9 years. Grundmann et al. (2003) emphasized the wide range of phenotypic variability caused by this DYT1 mutation. Wong et al. (2005) described a 10-year-old boy with the DYT1 deletion who had an unusual clinical presentation. At age 4 years, he presented with stiffness of the left ankle that progressed to the other leg. A year later he developed severe, painful myoclonic muscle spasms that were either spontaneous or precipitated by changes in posture, loud noises, or emotional upset, and were associated with profuse sweating. During these episodes, there was extreme truncal and limb stiffness and rigidity. EMG showed continuous motor unit activity during muscle spasms, suggestive of stiff-person syndrome (SPS; 184850), but no anti-GAD65 (138275) antibodies were found. He soon developed progressive dystonia and was wheelchair-bound by age 7 years. The patient experienced clinical improvement following plasmapheresis, which was unexplainable to the authors. His asymptomatic mother had the same DYT1 deletion, and a 13-year-old sister had type 1 diabetes mellitus (T1D; 222100) and was positive for anti-GAD65 antibodies. Wong et al. (2005) suggested a diagnosis of 'stiff-child syndrome,' but also considered that the patient may have had a phenotypic variation of primary torsion dystonia. Greene and Dauer (2006) suggested that the patient reported by Wong et al. (2005) had a severe form of DYT1 dystonia with painful limb dystonia. Arthrogryposis Multiplex Congenita 5 In 2 unrelated girls, each born of consanguineous Iranian parents (families 2 and 3), with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous 3-bp deletion (c.907_909del) in the TOR1A gene, resulting in the deletion of glu303 (E303del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant is present in heterozygous state only in 30 of 282,658 alleles in the gnomAD database. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. Functional studies of the variant and studies of patient cells were not performed. For discussion of the E303del mutation in the TOR1A gene, that was found in compound heterozygous state in a patient with AMC5 by Reichert et al. (2017), see 605204.0007. Variant Function Hewett et al. (2000) overexpressed wildtype and mutant (GAG-deleted) torsin-A in mouse neural CAD cells and observed the distribution pattern of the proteins by immunocytochemistry. The wildtype protein was found throughout the cytoplasm and neurites with a high degree of colocalization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. The authors hypothesized that if disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons. Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of 1 glutamic acid in the carboxyl terminus of the torsin-A protein. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wildtype protein. There is evidence that dysfunction of the dopamine system is implicated in the development of EOTD. Torres et al. (2004) studied the biologic function of torsin-A and its relation to dopaminergic neurotransmission. They showed that torsin-A can regulate the cellular trafficking of the dopamine transporter (126455), as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsin-A. The delta-Glu mutant causing dystonia did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in delta-Glu-torsin-A reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of the wildtype torsin-A through a mechanism presumably involving association of wildtype and mutant protein. Taken together, these results provided evidence for a functional role of torsin-A and for a loss of function and a dominant-negative phenotype of the delta-Glu-torsin-A mutation. These properties may contribute to the autosomal dominant nature of EOTD. Chen et al. (2010) showed that expression of human TOR1A with the delta-E mutation in C. elegans induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A expression against tunicamycin- or dithiothreitol-induced ER stress. In vitro cellular expression studies by Hettich et al. (2014) indicated that the delE303 mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype. (less)
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Pathogenic
(Jan 26, 2017)
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no assertion criteria provided
Method: clinical testing
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Dystonic disorder
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692306.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743604.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Sep 01, 2014)
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no assertion criteria provided
Method: literature only
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ARTHROGRYPOSIS MULTIPLEX CONGENITA 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV005046842.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment on evidence:
Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting … (more)
Torsion Dystonia 1, Autosomal Dominant In cases of early-onset torsion dystonia (DYT1; 128100), Ozelius et al. (1997) identified a heterozygous 3-bp deletion, GAG (delE302/303), resulting in the loss of 1 of a pair of conserved glutamic acid residues in a novel ATP-binding protein termed torsin-A. The GAG deletion was the only mutation detected in a large number of patients from different ethnic backgrounds. Most (90%) patients with an atypical presentation had no identifiable mutation in the DYT1 gene. At least 4 different background haplotypes were observed with the GAG deletion, indicating that the mutation had arisen more than once to cause ITD. Given the highly variable phenotype and reduced penetrance observed in ITD, the identification of the DYT1 mutation was a major advance for accurate diagnosis of the disorder. Because this mutation deletes one of 2 contiguous glutamic acid codons of the DYT1 gene, Goodchild and Dauer (2004) and Naismith et al. (2004) referred to it as delE302/303. Ikeuchi et al. (1999) described the apparently sporadic occurrence of primary torsion dystonia in a 25-year-old Japanese man who first noted at age 13 years that his left shoulder occasionally turned involuntarily to the left. By age 16 years his neck also became involved, twisting involuntarily to the left like his shoulder. He showed moderate improvement with diazepam (20 mg) and trihexyphenidyl (18 mg). Neither parent and none of the 4 grandparents showed any movement disorder or complained of writer's cramp. Nucleotide sequence analysis detected the GAG deletion in the patient's DYT1 gene. Restriction fragment length polymorphism (RFLP) analysis using BseRI showed that the GAG deletion was present not only in the patient but also in his mother, but not in his father. Kamm et al. (1999) examined 57 patients with idiopathic torsion dystonia for the 3-bp GAG deletion in the DYT1 gene. Three of 5 patients with early limb-onset torsion dystonia, one of them with a positive family history, tested positive for the mutation, as did 1 young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as 5 other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggested that the GAG deletion is responsible for most cases of typical early limb-onset dystonia, but not for other types of dystonia, in the German population studied. Hjermind et al. (2002) performed mutation analysis for the GAG deletion in the DYT1 gene in 107 unrelated Danish probands with primary torsion dystonia (37 were known familial cases). Clinical examinations showed that 22 probands had generalized dystonia (20 of whom had early limb-onset), 2 had hemidystonia, 5 had multifocal dystonia, 15 had segmental dystonia, and 63 had focal dystonia. Among the 107 probands investigated, the GAG deletion was only detected in 3 (2.8%) in whom the phenotype was typical. This corresponded to 15% of the 20 probands with early limb-onset generalized dystonia. Of the 3 probands with the GAG deletion, only 1 had familial dystonia, with the mutation detected in the affected father and in 6 asymptomatic adult relatives. In the second proband the DYT1 mutation was also encountered in the asymptomatic mother, while in the third case none of the parents had the GAG deletion and therefore represented a de novo mutation. Ikeuchi et al. (2002) studied 6 unrelated Japanese pedigrees with dystonia due to the GAG deletion in the DYT1 gene. None of the haplotypes in these families shared strong similarity to the Ashkenazi Jewish haplotype, suggesting that the GAG deletion occurred independently in the Japanese population. Some sharing was observed among haplotypes of the Japanese families, but there was nonetheless an indication of multiple independent events resulting in the deletion in these pedigrees. Among 256 patients with various subtypes of dystonia, Grundmann et al. (2003) identified 6 patients (2%) with the GAG deletion in the DYT1 gene. Two patients had classic features of early-onset primary generalized dystonia, 2 had multifocal dystonia (1 with involvement of cranial and cervical muscles), and 2 had only writer's cramp with slight progression. Apart from 1 patient with onset at 41 years, the mean age at onset was 9 years. Grundmann et al. (2003) emphasized the wide range of phenotypic variability caused by this DYT1 mutation. Wong et al. (2005) described a 10-year-old boy with the DYT1 deletion who had an unusual clinical presentation. At age 4 years, he presented with stiffness of the left ankle that progressed to the other leg. A year later he developed severe, painful myoclonic muscle spasms that were either spontaneous or precipitated by changes in posture, loud noises, or emotional upset, and were associated with profuse sweating. During these episodes, there was extreme truncal and limb stiffness and rigidity. EMG showed continuous motor unit activity during muscle spasms, suggestive of stiff-person syndrome (SPS; 184850), but no anti-GAD65 (138275) antibodies were found. He soon developed progressive dystonia and was wheelchair-bound by age 7 years. The patient experienced clinical improvement following plasmapheresis, which was unexplainable to the authors. His asymptomatic mother had the same DYT1 deletion, and a 13-year-old sister had type 1 diabetes mellitus (T1D; 222100) and was positive for anti-GAD65 antibodies. Wong et al. (2005) suggested a diagnosis of 'stiff-child syndrome,' but also considered that the patient may have had a phenotypic variation of primary torsion dystonia. Greene and Dauer (2006) suggested that the patient reported by Wong et al. (2005) had a severe form of DYT1 dystonia with painful limb dystonia. Arthrogryposis Multiplex Congenita 5 In 2 unrelated girls, each born of consanguineous Iranian parents (families 2 and 3), with arthrogryposis multiplex congenita-5 (AMC5; 618947), Kariminejad et al. (2017) identified a homozygous 3-bp deletion (c.907_909del) in the TOR1A gene, resulting in the deletion of glu303 (E303del). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. The variant is present in heterozygous state only in 30 of 282,658 alleles in the gnomAD database. None of the carrier parents had evidence of torsion dystonia, consistent with incomplete penetrance of the dominant phenotype. Functional studies of the variant and studies of patient cells were not performed. For discussion of the E303del mutation in the TOR1A gene, that was found in compound heterozygous state in a patient with AMC5 by Reichert et al. (2017), see 605204.0007. Variant Function Hewett et al. (2000) overexpressed wildtype and mutant (GAG-deleted) torsin-A in mouse neural CAD cells and observed the distribution pattern of the proteins by immunocytochemistry. The wildtype protein was found throughout the cytoplasm and neurites with a high degree of colocalization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. The authors hypothesized that if disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons. Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of 1 glutamic acid in the carboxyl terminus of the torsin-A protein. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wildtype protein. There is evidence that dysfunction of the dopamine system is implicated in the development of EOTD. Torres et al. (2004) studied the biologic function of torsin-A and its relation to dopaminergic neurotransmission. They showed that torsin-A can regulate the cellular trafficking of the dopamine transporter (126455), as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsin-A. The delta-Glu mutant causing dystonia did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in delta-Glu-torsin-A reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of the wildtype torsin-A through a mechanism presumably involving association of wildtype and mutant protein. Taken together, these results provided evidence for a functional role of torsin-A and for a loss of function and a dominant-negative phenotype of the delta-Glu-torsin-A mutation. These properties may contribute to the autosomal dominant nature of EOTD. Chen et al. (2010) showed that expression of human TOR1A with the delta-E mutation in C. elegans induced an ER stress response, even in the absence of additional stressors. Furthermore, expression of delta-E TOR1A with wildtype TOR1A in worms abrogated the protective effect of wildtype TOR1A expression against tunicamycin- or dithiothreitol-induced ER stress. In vitro cellular expression studies by Hettich et al. (2014) indicated that the delE303 mutant protein had an increased tendency to dimerize in the absence of reducing conditions, caused reduced processing of several proteins through the intracellular secretory pathway, decreased neurite extension, and caused vacuolization and morphologic changes in the endoplasmic reticulum and nuclear envelope compared to wildtype. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Early-onset generalized limb-onset dystonia
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000040443.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022
Comment:
Sometimes referred to as 904_906delGAG.
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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 |
---|---|---|---|---|
TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor. | Kariminejad A | Brain : a journal of neurology | 2017 | PMID: 29053766 |
Biallelic TOR1A variants in an infant with severe arthrogryposis. | Reichert SC | Neurology. Genetics | 2017 | PMID: 28516161 |
Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. | Demircioglu FE | eLife | 2016 | PMID: 27490483 |
DYT1 Early-Onset Isolated Dystonia. | Adam MP | - | 2016 | PMID: 20301665 |
Neuropathological features of genetically confirmed DYT1 dystonia: investigating disease-specific inclusions. | Paudel R | Acta neuropathologica communications | 2014 | PMID: 25403864 |
Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations. | Vulinovic F | Human mutation | 2014 | PMID: 24931141 |
Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A. | Hettich J | Human mutation | 2014 | PMID: 24930953 |
Regulation of Torsin ATPases by LAP1 and LULL1. | Zhao C | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23569223 |
Genetic and clinical features of primary torsion dystonia. | Ozelius LJ | Neurobiology of disease | 2011 | PMID: 21168499 |
The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response. | Chen P | Human molecular genetics | 2010 | PMID: 20584926 |
Interaction of torsinA with its major binding partners is impaired by the dystonia-associated DeltaGAG deletion. | Naismith TV | The Journal of biological chemistry | 2009 | PMID: 19651773 |
LULL1 retargets TorsinA to the nuclear envelope revealing an activity that is impaired by the DYT1 dystonia mutation. | Vander Heyden AB | Molecular biology of the cell | 2009 | PMID: 19339278 |
Consequences of the DYT1 mutation on torsinA oligomerization and degradation. | Gordon KL | Neuroscience | 2008 | PMID: 18940237 |
Stiff child syndrome with mutation of DYT1 gene. | Greene PE | Neurology | 2006 | PMID: 16682692 |
Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. | Goodchild RE | Neuron | 2005 | PMID: 16364897 |
Stiff child syndrome with mutation of DYT1 gene. | Wong VC | Neurology | 2005 | PMID: 16275837 |
Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. | Torres GE | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15505207 |
TorsinA in the nuclear envelope. | Naismith TV | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15136718 |
Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. | Goodchild RE | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 14711988 |
Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. | Grundmann K | Archives of neurology | 2003 | PMID: 12975293 |
Multiple founder effects in Japanese families with primary torsion dystonia harboring the GAG deletion in the Tor1A (DYT1) gene. | Ikeuchi T | Neurogenetics | 2002 | PMID: 12481989 |
Inherited and de novo mutations in sporadic cases of DYT1-dystonia. | Hjermind LE | European journal of human genetics : EJHG | 2002 | PMID: 11973627 |
Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells. | Hewett J | Human molecular genetics | 2000 | PMID: 10814722 |
Genetic testing for early-onset torsion dystonia (DYT1): introduction of a simple screening method, experiences from testing of a large patient cohort, and ethical aspects. | Klein C | Genetic testing | 1999 | PMID: 10627938 |
A case of primary torsion dystonia in Japan with the 3-bp (GAG) deletion in the DYT1 gene with a unique clinical presentation. | Ikeuchi T | Neurogenetics | 1999 | PMID: 10541594 |
GAG deletion in the DYT1 gene in early limb-onset idiopathic torsion dystonia in Germany. | Kamm C | Movement disorders : official journal of the Movement Disorder Society | 1999 | PMID: 10435508 |
Phenotypic variability of the DYT1 mutation in German dystonia patients. | Leube B | Acta neurologica Scandinavica | 1999 | PMID: 10225357 |
The role of DYT1 in primary torsion dystonia in Europe. | Valente EM | Brain : a journal of neurology | 1998 | PMID: 9874484 |
De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia. | Klein C | Human molecular genetics | 1998 | PMID: 9618171 |
The molecular genetics of the dystonias. | Warner TT | Journal of neurology, neurosurgery, and psychiatry | 1998 | PMID: 9576529 |
The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. | Ozelius LJ | Nature genetics | 1997 | PMID: 9288096 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TOR1A | - | - | - | - |
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Text-mined citations for rs80358233 ...
HelpRecord last updated Aug 25, 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.