TOR1A

torsin family 1 member A, the group of Torsins

Basic information

Region (hg38): 9:129812941-129824244

Previous symbols: [ "DYT1" ]

Links

ENSG00000136827 ∙ NCBI:1861 ∙ OMIM:605204 ∙ HGNC:3098 ∙ Uniprot:O14656 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• early-onset generalized limb-onset dystonia (Supportive), mode of inheritance: AD
• early-onset generalized limb-onset dystonia (Moderate), mode of inheritance: AD
• arthrogryposis multiplex congenita 5 (Moderate), mode of inheritance: AR
• early-onset generalized limb-onset dystonia (Strong), mode of inheritance: AD
• arthrogryposis multiplex congenita 5 (Strong), mode of inheritance: AR
• early-onset generalized limb-onset dystonia (Strong), mode of inheritance: AD
• early-onset generalized limb-onset dystonia (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dystonia 1, torsion; Arthrogryposis multiplex congenita 5	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Musculoskeletal; Neurologic	9288096; 10541594; 10435508; 11523564; 12391355; 11973627; 12481989; 12402271; 12975293; 15326234; 16275837; 17503336; 18519876; 19955557; 20925076; 21515903; 22132914; 28516161; 29053766; 30244176

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TOR1A gene.

• Dystonic disorder (82 variants)
• Early-onset generalized limb-onset dystonia (62 variants)
• not provided (52 variants)
• Inborn genetic diseases (12 variants)
• not specified (8 variants)
• Arthrogryposis multiplex congenita 5 (6 variants)
• Early-onset generalized limb-onset dystonia;Arthrogryposis multiplex congenita 5 (3 variants)
• TOR1A-related condition (3 variants)
• Arthrogryposis multiplex congenita 5;Early-onset generalized limb-onset dystonia (1 variants)
• Flexion contracture (1 variants)
• Dystonia 1, torsion, late-onset (1 variants)
• TOR1A-related disorders (1 variants)
• Dystonia 1, torsion, modifier of (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TOR1A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	26	2	31
missense	1	1	51	4	1	58
nonsense	2	2	4			8
start loss						0
frameshift		1	3			4
inframe indel		1	2			3
splice donor/acceptor (+/-2bp)		1	1			2
splice region			4	1	1	6
non coding			19	19	19	57
Total	3	6	83	49	22

Highest pathogenic variant AF is 0.00000657

Variants in TOR1A

This is a list of pathogenic ClinVar variants found in the TOR1A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-129812962-T-C		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 13, 2018)
9-129812970-G-A		Early-onset generalized limb-onset dystonia	Benign (Jan 13, 2018)
9-129812975-C-T		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 12, 2018)
9-129813011-A-T		Early-onset generalized limb-onset dystonia	Benign (Jan 13, 2018)
9-129813024-G-A		Early-onset generalized limb-onset dystonia	Benign (Jan 12, 2018)
9-129813038-T-C		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 12, 2018)
9-129813042-A-T		Early-onset generalized limb-onset dystonia	Likely benign (Jan 12, 2018)
9-129813071-AAAT-A		Early-onset generalized limb-onset dystonia	Uncertain significance (Jun 14, 2016)
9-129813093-G-T		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 13, 2018)
9-129813140-C-T		Early-onset generalized limb-onset dystonia	Uncertain significance (Apr 28, 2017)
9-129813141-G-A		Early-onset generalized limb-onset dystonia	Benign (Jan 13, 2018)
9-129813147-GC-G		Early-onset generalized limb-onset dystonia	Likely benign (Jun 14, 2016)
9-129813160-G-C		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 13, 2018)
9-129813187-C-T		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 13, 2018)
9-129813349-G-A		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 12, 2018)
9-129813518-A-T		Early-onset generalized limb-onset dystonia	Benign (Jan 12, 2018)
9-129813548-TA-T		Early-onset generalized limb-onset dystonia	Likely benign (Jun 14, 2016)
9-129813556-A-C		Early-onset generalized limb-onset dystonia	Benign (Jan 12, 2018)
9-129813556-A-AC		Early-onset generalized limb-onset dystonia	Likely benign (Jun 14, 2016)
9-129813557-AC-A		Early-onset generalized limb-onset dystonia	Likely benign (Jun 14, 2016)
9-129813558-C-A		Early-onset generalized limb-onset dystonia	Benign (Jan 13, 2018)
9-129813627-G-A		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 13, 2018)
9-129813756-G-A		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 12, 2018)
9-129813758-G-C		Early-onset generalized limb-onset dystonia	Benign (Aug 26, 2018)
9-129813771-C-T		Early-onset generalized limb-onset dystonia	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TOR1A	protein_coding	protein_coding	ENST00000351698	5	11191

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000506	0.891	125724	0	24	125748	0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.535	160	180	0.888	0.00000992	2198
Missense in Polyphen		60	71.364	0.84076		896
Synonymous	-0.0862	77	76.0	1.01	0.00000481	626
Loss of Function	1.43	7	12.4	0.563	7.25e-7	149

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000867	0.0000867
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.000158	0.000158
Middle Eastern	0.000109	0.000109
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non- neural tissues. {ECO:0000269|PubMed:15505207, ECO:0000269|PubMed:16361107, ECO:0000269|PubMed:17428918, ECO:0000269|PubMed:18167355, ECO:0000269|PubMed:18827015, ECO:0000269|PubMed:19339278, ECO:0000269|PubMed:20169475, ECO:0000269|PubMed:23569223}.
• Disease: DISEASE: Dystonia 1, torsion, autosomal dominant (DYT1) [MIM:128100]: A primary torsion dystonia, and the most common and severe form. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Dystonia type 1 is characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body, in the absence of other neurological symptoms. Typically, symptoms develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. 'Torsion' refers to the twisting nature of body movements observed in DYT1, often affecting the trunk. Distribution and severity of symptoms vary widely between affected individuals, ranging from mild focal dystonia to severe generalized dystonia, even within families. {ECO:0000269|PubMed:14970196, ECO:0000269|PubMed:15505207, ECO:0000269|PubMed:16361107, ECO:0000269|PubMed:17428918, ECO:0000269|PubMed:18167355, ECO:0000269|PubMed:18477710, ECO:0000269|PubMed:18827015, ECO:0000269|PubMed:19955557, ECO:0000269|PubMed:20169475, ECO:0000269|PubMed:21102408, ECO:0000269|PubMed:27490483, ECO:0000269|PubMed:9288096}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Vesicle-mediated transport;Membrane Trafficking;Clathrin-mediated endocytosis;Cargo recognition for clathrin-mediated endocytosis;Alpha-synuclein signaling (Consensus)

Recessive Scores

• pRec: 0.328

Intolerance Scores

• loftool: 0.524
• rvis_EVS: -0.18
• rvis_percentile_EVS: 39.95

Haploinsufficiency Scores

• pHI: 0.680
• hipred: Y
• hipred_score: 0.568
• ghis: 0.581

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Tor1a
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: protein deneddylation;response to oxidative stress;organelle organization;nuclear envelope organization;cell adhesion;neuron projection development;protein localization to nucleus;wound healing, spreading of cells;intermediate filament cytoskeleton organization;synaptic vesicle transport;chaperone cofactor-dependent protein refolding;protein homooligomerization;regulation of dopamine uptake involved in synaptic transmission;chaperone-mediated protein folding;ER-associated misfolded protein catabolic process;nuclear membrane organization;chaperone-mediated protein transport;positive regulation of synaptic vesicle endocytosis;regulation of protein localization to cell surface
• Cellular component: nuclear envelope;endoplasmic reticulum;endoplasmic reticulum lumen;cytosol;cytoskeleton;synaptic vesicle;membrane;cell junction;secretory granule;growth cone;cytoplasmic vesicle membrane;nuclear membrane;extrinsic component of endoplasmic reticulum membrane;intracellular membrane-bounded organelle;extracellular exosome
• Molecular function: protein binding;ATP binding;cytoskeletal protein binding;ATPase activity;kinesin binding;unfolded protein binding;misfolded protein binding