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

gnomAD frequency: 0.00014  dbSNP: rs267607134

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000296896	SCV000329552	likely pathogenic	not provided	2024-08-24	criteria provided, single submitter	clinical testing	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)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000296896	SCV000610735	uncertain significance	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808573	SCV000948685	uncertain significance	Dystonic disorder	2025-01-14	criteria provided, single submitter	clinical testing	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 TOR1A-related conditions (PMID: 19955557, 36757831). ClinVar contains an entry for this variant (Variation ID: 18438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825647	SCV000967017	uncertain significance	not specified	2019-01-11	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000258917	SCV001530109	uncertain significance	Early-onset generalized limb-onset dystonia	2018-02-07	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000296896	SCV002564074	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TOR1A: PS3:Moderate, PS4:Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825647	SCV005203629	uncertain significance	not specified	2024-07-05	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000005491	SCV000025673	pathogenic	Dystonia 1, torsion, late-onset	2014-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000258917	SCV000328700	not provided	Early-onset generalized limb-onset dystonia		no assertion provided	literature only