Submissions for variant NM_000113.3(TOR1A):c.904GAG[1] (p.Glu303del)

dbSNP: rs80358233

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000584141	SCV000283510	pathogenic	Dystonic disorder	2024-12-24	criteria provided, single submitter	clinical testing	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 autosomal dominant 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 gene product 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.
GeneDx	RCV000412981	SCV000491317	pathogenic	not provided	2020-06-09	criteria provided, single submitter	clinical testing	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)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000005488	SCV000778594	likely pathogenic	Early-onset generalized limb-onset dystonia	2018-05-10	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000412981	SCV000854896	pathogenic	not provided	2018-03-21	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000005488	SCV001150297	pathogenic	Early-onset generalized limb-onset dystonia	2019-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000412981	SCV001248848	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TOR1A: PM6:Strong, PP1:Strong, PM4:Supporting, PS3:Supporting
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000005488	SCV001434932	pathogenic	Early-onset generalized limb-onset dystonia	2018-08-13	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV001266579	SCV001444755	pathogenic	Inborn genetic diseases	2023-11-17	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000005488	SCV001530110	pathogenic	Early-onset generalized limb-onset dystonia	2024-02-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000412981	SCV001762213	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000005488	SCV002011944	pathogenic	Early-onset generalized limb-onset dystonia	2021-10-02	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000412981	SCV002022386	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000005488	SCV002581776	pathogenic	Early-onset generalized limb-onset dystonia	2022-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504750	SCV002815146	pathogenic	Early-onset generalized limb-onset dystonia; Arthrogryposis multiplex congenita 5	2021-10-15	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335014	SCV004046095	pathogenic	TOR1A-related disorder		criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000005488	SCV004101509	pathogenic	Early-onset generalized limb-onset dystonia	2023-06-02	criteria provided, single submitter	clinical testing	he inframe deletion c.907_909del(p.Glu303del) variant in TOR1A gene has been observed in heterozygous state in individual(s) with early onset primary dystonia (Hettich et. al., 2014; Vulinovic et. al., 2014). In at least one individual the variant was observed to be de novo. Experimental studies have shown that this variant affects TOR1A function (Hettich et. al., 2014; Vulinovic et. al., 201). The observed variant has allele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This p.Glu303del causes deletion of amino acid Glutamic Acid at position 303. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000005488	SCV004801528	pathogenic	Early-onset generalized limb-onset dystonia	2022-02-15	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003335014	SCV005200910	pathogenic	TOR1A-related disorder	2024-06-24	criteria provided, single submitter	clinical testing	PS3, PS4, PM4
OMIM	RCV000005488	SCV000025670	pathogenic	Early-onset generalized limb-onset dystonia	2014-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000005488	SCV000040443	not provided	Early-onset generalized limb-onset dystonia		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000584141	SCV000692306	pathogenic	Dystonic disorder	2017-01-26	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000412981	SCV001743604	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412981	SCV001951695	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003335014	SCV004116561	pathogenic	TOR1A-related disorder	2024-09-06	no assertion criteria provided	clinical testing	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). In addition, this variant in the homozygous state is associated with arthrogryposis, developmental delay, strabismus, and tremor (Kariminejad et al., 2017. PubMed ID: 29053766; Saffari et al., 2023. PubMed ID: 36757831). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD 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.
OMIM	RCV004558237	SCV005046842	pathogenic	Arthrogryposis multiplex congenita 5	2014-09-01	no assertion criteria provided	literature only