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

gnomAD frequency: 0.00003  dbSNP: rs760768475

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000677723	SCV000803877	likely pathogenic	Early-onset generalized limb-onset dystonia	2017-03-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001592856	SCV001815050	likely pathogenic	not provided	2021-04-14	criteria provided, single submitter	clinical testing	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)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000677723	SCV001976705	pathogenic	Early-onset generalized limb-onset dystonia	2021-10-01	criteria provided, single submitter	clinical testing	PVS1, PP3, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV001250912	SCV002765071	likely pathogenic	Arthrogryposis multiplex congenita 5	2022-11-24	criteria provided, single submitter	clinical testing	This variant was identified as homozygous._x000D_ Criteria applied: PVS1_STR, PM3, PM2_SUP
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001250912	SCV003806747	pathogenic	Arthrogryposis multiplex congenita 5	2022-09-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 supporting, PM3 supporting
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001250912	SCV003922270	pathogenic	Arthrogryposis multiplex congenita 5	2023-05-02	criteria provided, single submitter	curation	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).
CeGaT Center for Human Genetics Tuebingen	RCV001592856	SCV004010874	likely pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	TOR1A: PVS1:Strong, PM2
OMIM	RCV001250912	SCV001426389	pathogenic	Arthrogryposis multiplex congenita 5	2020-07-31	no assertion criteria provided	literature only
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001250912	SCV004099348	pathogenic	Arthrogryposis multiplex congenita 5	2023-10-30	no assertion criteria provided	clinical testing