VCV000018438.38 - ClinVar

NM_000113.3(TOR1A):c.613T>A (p.Phe205Ile)

Germline

Classification

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.

(9)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000113.3(TOR1A):c.613T>A (p.Phe205Ile)

Variation ID: 18438 Accession: VCV000018438.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.11 9: 129818752 (GRCh38) [ NCBI UCSC ] 9: 132581031 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Nov 22, 2016	Dec 22, 2024	Aug 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000113.3:c.613T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000104.1:p.Phe205Ile	missense
NC_000009.12:g.129818752A>T
NC_000009.11:g.132581031A>T
NG_008049.1:g.10411T>A
LRG_1029:g.10411T>A
LRG_1029t1:c.613T>A	LRG_1029p1:p.Phe205Ile
	O14656:p.Phe205Ile

... more HGVS ... less HGVS

Protein change

F205I

Other names

Canonical SPDI

NC_000009.12:129818751:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD) 0.00014

Links

ClinGen: CA117320 UniProtKB: O14656#VAR_070932 OMIM: 605204.0004 dbSNP: rs267607134 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TOR1A		-	-	GRCh38 GRCh37	198	261

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.
Early-onset generalized limb-onset dystonia	Uncertain significance (2)	criteria provided, single submitter	Feb 7, 2018	RCV000258917.11
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Aug 24, 2024	RCV000296896.32
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 5, 2024	RCV000825647.13
Dystonic disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 25, 2023	RCV000808573.17
Dystonia 1, torsion, late-onset	Pathogenic (1)	no assertion criteria provided	Sep 1, 2014	RCV000005491.13

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.
Uncertain significance (Jan 11, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967017.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (4) PubMed: 24930953‚ 24931141‚ 19955557‚ 27168150 Comment: Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe205Ile variant in TOR1A has been reported in 1 individual with late-onset focal dyston ia (Calakos … (more) Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe205Ile variant in TOR1A has been reported in 1 individual with late-onset focal dyston ia (Calakos 2010), but was also identified in 0.01% (13/129134) of European chro mosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support that the variant impacts protein function (Het tich 2014). However, these types of assays may not accurately represent biologic al function. A knock-in mouse model suggests that this variant results in reduce d levels of the TOR1A protein (Bhagat 2016). Furthermore, homozygous p.Phe205Ile knock-in mice exhibit motor impairment and altered synaptic plasticity (Bhagat 2016). However, given that these phenotypes were only observed in homozygous ani mals, it remains unclear if this variant would be expected to cause autosomal do minant primary-onset dystonia. In summary, while there is suspicion for a pathog enic role, the clinical significance of the p.Phe205Ile variant is uncertain. AC MG/AMP Criteria applied: PS3_Moderate, PP3. (less) Number of individuals with the variant: 1
Uncertain significance (Jul 05, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005203629.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (7) PubMed: 30363439‚ 24930953‚ 32243914‚ 27168150‚ 19955557‚ 31583275‚ 36757831 Comment: Variant summary: TOR1A c.613T>A (p.Phe205Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: TOR1A c.613T>A (p.Phe205Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250734 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TOR1A causing TOR1A Related Disorders, allowing no conclusion about variant significance. c.613T>A has been reported in the literature in individuals affected with TOR1A Related Disorders (e.g. Calakos_2010, Saffari_2023, Gustavsson_2017). These report(s) do not provide unequivocal conclusions about association of the variant with TOR1A Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in motor impairment in mice that are homozygous for the variant (Bhagat_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27168150, 19955557, 30363439, 24930953, 31583275, 32243914, 36757831). ClinVar contains an entry for this variant (Variation ID: 18438). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Uncertain significance (Sep 19, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610735.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Uncertain significance (Feb 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Early-onset generalized limb-onset dystonia Affected status: yes Allele origin: paternal	Baylor Genetics Accession: SCV001530109.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Oct 25, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dystonic disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000948685.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 19955557‚ 24930953‚ 27168150‚ 32243914 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 205 of the TOR1A protein (p.Phe205Ile). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 205 of the TOR1A protein (p.Phe205Ile). This variant is present in population databases (rs267607134, gnomAD 0.01%). This missense change has been observed in individual(s) with late-onset focal dystonia (PMID: 19955557). ClinVar contains an entry for this variant (Variation ID: 18438). 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 TOR1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TOR1A function (PMID: 19955557, 24930953, 27168150, 32243914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Aug 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329552.10 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Identified in a patient with late-onset focal dystonia in the published literature (PMID: 19955557); Observed with a TOR1A variant on the opposite allele (in trans) … (more) Identified in a patient with late-onset focal dystonia in the published literature (PMID: 19955557); Observed with a TOR1A variant on the opposite allele (in trans) in a patient with developmental delay, movement disorder, and spasticity in published literature (PMID: 36757831); Published functional studies demonstrate a damaging effect: cell culture studies show the variant produced frequent inclusion bodies and affected the function of the TOR1A protein; in addition, in vitro studies demonstrate the variant had increased tendency to dimerize, showed altered nuclear morphology, and compromised neurite extension in human neuroblastoma cells (PMID: 19955557, 24930953); 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: 27168150, 24862462, 24930953, 28432771, 31090117, 24931141, 32243914, 32289333, 19955557, 36757831, 20301665, 30877032, 31583275) (less)
Uncertain significance (Jul 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002564074.17 First in ClinVar: Aug 23, 2022 Last updated: Dec 22, 2024	Comment: TOR1A: PS3:Moderate, PS4:Moderate Number of individuals with the variant: 1
Pathogenic (Sep 01, 2014)	no assertion criteria provided Method: literature only	DYSTONIA 1, TORSION, LATE-ONSET Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025673.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2017	Publications: PubMed (2) PubMed: 19955557‚ 24930953 Comment on evidence: In a man with late-onset focal torsion dystonia (DYT1; 128100) of the oromandibular region, Calakos et al. (2010) identified a heterozygous 613T-A transversion in exon … (more) In a man with late-onset focal torsion dystonia (DYT1; 128100) of the oromandibular region, Calakos et al. (2010) identified a heterozygous 613T-A transversion in exon 3 of the TOR1A gene, resulting in a phe205-to-ile (F205I) substitution in a highly conserved residue in the beta-strand motif in the AAA domain. The mutation was not found in 1,600 control chromosomes. The patient had onset of involuntary jaw movements and grimacing in his fifth decade. Neurologic examination showed cogwheel tone without rigidity and mild action tremor in the upper limbs, as well as absent ankle reflexes. He had a history of bipolar disorder, treatment with lithium, and remote history of treatment with a dopamine receptor blocking agent. There was a family history of tremor and depression, but no family history of dystonia. In vitro functional expression studies in cultured cells showed that the F205I-mutant protein produced TOR1A inclusion bodies that colocalized with the endoplasmic reticulum in about 44% of cells. Transfection of the common GAGdel mutation (605204.0001) produced inclusions in 79% of cells, and wildtype TOR1A produced inclusions in about 10% of cells. The findings suggested that the F205I mutation had impaired function that differed from the GAGdel mutation, and that F205I may contribute to the milder phenotype in this patient. In vitro cellular expression studies by Hettich et al. (2014) indicated that the F205I 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)
not provided (-)	no classification provided Method: literature only	Early-onset generalized limb-onset dystonia Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000328700.2 First in ClinVar: Nov 22, 2016 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1492 BookShelf: NBK1492

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Phe205Ile variant in TOR1A has been reported in 1 individual with late-onset focal dyston ia (Calakos 2010), but was also identified in 0.01% (13/129134) of European chro mosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction t ools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support that the variant impacts protein function (Het tich 2014). However, these types of assays may not accurately represent biologic al function. A knock-in mouse model suggests that this variant results in reduce d levels of the TOR1A protein (Bhagat 2016). Furthermore, homozygous p.Phe205Ile knock-in mice exhibit motor impairment and altered synaptic plasticity (Bhagat 2016). However, given that these phenotypes were only observed in homozygous ani mals, it remains unclear if this variant would be expected to cause autosomal do minant primary-onset dystonia. In summary, while there is suspicion for a pathog enic role, the clinical significance of the p.Phe205Ile variant is uncertain. AC MG/AMP Criteria applied: PS3_Moderate, PP3.

Comment:

Variant summary: TOR1A c.613T>A (p.Phe205Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250734 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TOR1A causing TOR1A Related Disorders, allowing no conclusion about variant significance. c.613T>A has been reported in the literature in individuals affected with TOR1A Related Disorders (e.g. Calakos_2010, Saffari_2023, Gustavsson_2017). These report(s) do not provide unequivocal conclusions about association of the variant with TOR1A Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in motor impairment in mice that are homozygous for the variant (Bhagat_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27168150, 19955557, 30363439, 24930953, 31583275, 32243914, 36757831). ClinVar contains an entry for this variant (Variation ID: 18438). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 205 of the TOR1A protein (p.Phe205Ile). This variant is present in population databases (rs267607134, gnomAD 0.01%). This missense change has been observed in individual(s) with late-onset focal dystonia (PMID: 19955557). ClinVar contains an entry for this variant (Variation ID: 18438). 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 TOR1A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TOR1A function (PMID: 19955557, 24930953, 27168150, 32243914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Identified in a patient with late-onset focal dystonia in the published literature (PMID: 19955557); Observed with a TOR1A variant on the opposite allele (in trans) in a patient with developmental delay, movement disorder, and spasticity in published literature (PMID: 36757831); Published functional studies demonstrate a damaging effect: cell culture studies show the variant produced frequent inclusion bodies and affected the function of the TOR1A protein; in addition, in vitro studies demonstrate the variant had increased tendency to dimerize, showed altered nuclear morphology, and compromised neurite extension in human neuroblastoma cells (PMID: 19955557, 24930953); 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: 27168150, 24862462, 24930953, 28432771, 31090117, 24931141, 32243914, 32289333, 19955557, 36757831, 20301665, 30877032, 31583275)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.	Saffari A	Brain : a journal of neurology	2023	PMID: 36757831
Cellular analysis of a novel mutation p. Ser287Tyr in TOR1A in late-onset isolated dystonia.	Xu L	Neurobiology of disease	2020	PMID: 32243914
Epidemiology of DYT1 dystonia: Estimating prevalence via genetic ascertainment.	Park J	Neurology. Genetics	2019	PMID: 31583275
Genetic Identification in Early Onset Parkinsonism among Norwegian Patients.	Gustavsson EK	Movement disorders clinical practice	2017	PMID: 30363439
Mouse model of rare TOR1A variant found in sporadic focal dystonia impairs domains affected in DYT1 dystonia patients and animal models.	Bhagat SL	Neurobiology of disease	2016	PMID: 27168150
DYT1 Early-Onset Isolated Dystonia.	Adam MP	-	2016	PMID: 20301665
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
Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia.	Calakos N	Journal of medical genetics	2010	PMID: 19955557

Text-mined citations for rs267607134 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000113.3(TOR1A):c.613T>A (p.Phe205Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267607134 ...