VCV000559927.21 - ClinVar

NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)

Variation ID: 559927 Accession: VCV000559927.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.11 9: 129814109 (GRCh38) [ NCBI UCSC ] 9: 132576388 (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	Aug 25, 2018	Oct 20, 2024	Jun 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000113.3:c.862C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000104.1:p.Arg288Ter	nonsense
NC_000009.12:g.129814109G>A
NC_000009.11:g.132576388G>A
NG_008049.1:g.15054C>T
LRG_1029:g.15054C>T
LRG_1029t1:c.862C>T	LRG_1029p1:p.Arg288Ter

... more HGVS ... less HGVS

Protein change

R288*

Other names

NM_000113.3(TOR1A):c.862C>T
p.Arg288Ter

Canonical SPDI

NC_000009.12:129814108:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

OMIM: 605204.0008 dbSNP: rs760768475 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	194	257

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	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2021	RCV000677723.10
Arthrogryposis multiplex congenita 5	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 2, 2023	RCV001250912.12
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 1, 2023	RCV001592856.20

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.
Likely pathogenic (Mar 22, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Early-onset generalized limb-onset dystonia Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803877.1 First in ClinVar: Aug 25, 2018 Last updated: Aug 25, 2018
Likely pathogenic (Apr 14, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001815050.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been … (more) Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31589614, 30877032, 26297380, 32399599, 30244176) (less)
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Early-onset generalized limb-onset dystonia Affected status: yes Allele origin: unknown	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV001976705.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Publications: PubMed (1) PubMed: 34008892 Comment: PVS1, PP3, PP5
Likely pathogenic (Nov 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis multiplex congenita 5 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002765071.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: This variant was identified as homozygous._x000D_ Criteria applied: PVS1_STR, PM3, PM2_SUP
Pathogenic (Sep 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis multiplex congenita 5 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806747.2 First in ClinVar: Mar 04, 2023 Last updated: May 06, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 supporting, PM3 supporting Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (May 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Arthrogryposis multiplex congenita 5 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003922270.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: The homozygous p.Arg288Ter variant in TOR1A was identified by our study in one individual with arthrogryposis multiplex congenita. The p.Arg288Ter variant in TOR1A has been … (more) The homozygous p.Arg288Ter variant in TOR1A was identified by our study in one individual with arthrogryposis multiplex congenita. The p.Arg288Ter variant in TOR1A has been previously reported in 8 unrelated individuals with arthrogryposis multiplex congenita 15 (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1) and segregated with disease in 2 affected siblings from one family (PMID: 32399599), but has been identified in 0.005% (6/113760) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs760768475). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 previously reported unrelated individuals (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1), six were homozygotes (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1) and two were compound heterozygotes who carried pathogenic variants in trans (PMID: 36757831, ClinVar Variation ID: 5180), which increases the likelihood that the p.Arg288Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 559927) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 288. This alteration occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TOR1A gene is an established disease mechanism in autosomal recessive arthrogryposis multiplex congenita 15. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive arthrogryposis multiplex congenita 15. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting (Richards 2015). (less)
Likely pathogenic (Jun 01, 2023)	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: SCV004010874.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: TOR1A: PVS1:Strong, PM2 Number of individuals with the variant: 1
Pathogenic (Jul 31, 2020)	no assertion criteria provided Method: literature only	ARTHROGRYPOSIS MULTIPLEX CONGENITA 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001426389.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020	Publications: PubMed (1) PubMed: 30244176 Comment on evidence: In a 4.5-month-old boy, born of reportedly unrelated Bulgarian parents, with arthrogryposis multiplex congenita-5 (AMC5; 618947), Isik et al. (2019) identified a homozygous c.862C-T transition … (more) In a 4.5-month-old boy, born of reportedly unrelated Bulgarian parents, with arthrogryposis multiplex congenita-5 (AMC5; 618947), Isik et al. (2019) identified a homozygous c.862C-T transition in exon 5 of the TOR1A gene, resulting in an arg288-to-ter (R288X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was found at a low frequency in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. The infant died of cardiorespiratory failure. (less)
Pathogenic (Oct 30, 2023)	no assertion criteria provided Method: clinical testing	Arthrogryposis multiplex congenita 5 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004099348.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31589614, 30877032, 26297380, 32399599, 30244176)

Comment:

The homozygous p.Arg288Ter variant in TOR1A was identified by our study in one individual with arthrogryposis multiplex congenita. The p.Arg288Ter variant in TOR1A has been previously reported in 8 unrelated individuals with arthrogryposis multiplex congenita 15 (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1) and segregated with disease in 2 affected siblings from one family (PMID: 32399599), but has been identified in 0.005% (6/113760) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs760768475). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 8 previously reported unrelated individuals (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1), six were homozygotes (PMID: 34008892, PMID: 36757831, PMID: 32399599, PMID: 30244176, ClinVar SCV002765071.1) and two were compound heterozygotes who carried pathogenic variants in trans (PMID: 36757831, ClinVar Variation ID: 5180), which increases the likelihood that the p.Arg288Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 559927) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 288. This alteration occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TOR1A gene is an established disease mechanism in autosomal recessive arthrogryposis multiplex congenita 15. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive arthrogryposis multiplex congenita 15. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting (Richards 2015).

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
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.	Marinakis NM	American journal of medical genetics. Part A	2021	PMID: 34008892
Biallelic TOR1A mutations cause severe arthrogryposis: A case requiring reverse phenotyping.	Isik E	European journal of medical genetics	2019	PMID: 30244176

Text-mined citations for rs760768475 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs760768475 ...