rs724159981

Positions:

• chr9-129814061-TCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4_Supporting PP5

The NM_000113.3(TOR1A):​c.907_909del​(p.Glu303del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000052 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: TOR1A NM_000113.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23 U:1 O:1
• Conservation: PhyloP100: 4.74

Genes affected

TOR1A (HGNC:3098): (torsin family 1 member A) The protein encoded by this gene is a member of the AAA family of adenosine triphosphatases (ATPases), is related to the Clp protease/heat shock family and is expressed prominently in the substantia nigra pars compacta. Mutations in this gene result in the autosomal dominant disorder, torsion dystonia 1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000113.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-129814061-TCTC-T is Pathogenic according to our data. Variant chr9-129814061-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5180.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=16}. Variant chr9-129814061-TCTC-T is described in Lovd as [Pathogenic]. Variant chr9-129814061-TCTC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1A	NM_000113.3	c.907_909del	p.Glu303del	inframe_deletion	5/5	ENST00000351698.5	NP_000104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1A	ENST00000351698.5	c.907_909del	p.Glu303del	inframe_deletion	5/5	1	NM_000113.3	ENSP00000345719	P1
TOR1A	ENST00000651202.1	c.*175_*177del		3_prime_UTR_variant	6/6			ENSP00000498222
TOR1A	ENST00000474192.1	n.491_493del		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251492 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461892 Hom.: 0 AF XY: 0.0000509 AC XY: 37 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:23 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Early-onset generalized limb-onset dystonia Pathogenic:8 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 13, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 15, 2022	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 13, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 10, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 02, 2023	The missense variant c.5879G>T(p.Arg1960Leu) in SCN8A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant is absent in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - benign, SIFT - tolerated and MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid change p.Arg1960Leu in SCN8A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 1960 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TOR1A: PM6:Strong, PP1:Strong, PM4:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	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) -

TOR1A-related disorder Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 06, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 24, 2024	PS3, PS4, PM4 -

Dystonic disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 26, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

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. -

Arthrogryposis multiplex congenita 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2014

- -

Early-onset generalized limb-onset dystonia;C5436453:Arthrogryposis multiplex congenita 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80358233; hg19: chr9-132576340;