chr9-129818752-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000113.3(TOR1A):c.613T>A(p.Phe205Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000113.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TOR1A | ENST00000351698.5 | c.613T>A | p.Phe205Ile | missense_variant | Exon 3 of 5 | 1 | NM_000113.3 | ENSP00000345719.4 | ||
TOR1A | ENST00000651202.1 | c.709T>A | p.Phe237Ile | missense_variant | Exon 3 of 6 | ENSP00000498222.1 | ||||
TOR1A | ENST00000473604.2 | n.723T>A | non_coding_transcript_exon_variant | Exon 3 of 4 | 5 | |||||
TOR1A | ENST00000474192.1 | n.30T>A | non_coding_transcript_exon_variant | Exon 1 of 3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250734Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135604
GnomAD4 exome AF: 0.000238 AC: 348AN: 1461154Hom.: 0 Cov.: 33 AF XY: 0.000221 AC XY: 161AN XY: 726934
GnomAD4 genome AF: 0.000125 AC: 19AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74340
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
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) -
PS3_Supporting, PM2 -
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TOR1A: PS3:Moderate, PS4:Moderate -
not specified Uncertain:2
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. -
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. -
Early-onset generalized limb-onset dystonia Uncertain:1Other:1
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This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Dystonia 1, torsion, late-onset Pathogenic:1
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Dystonic disorder Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at