rs575326605
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5
The NM_000360.4(TH):c.1228C>T(p.Arg410Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000627 in 1,611,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R410L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.1228C>T | p.Arg410Trp | missense_variant | 12/13 | ENST00000352909.8 | |
TH | NM_199292.3 | c.1321C>T | p.Arg441Trp | missense_variant | 13/14 | ||
TH | NM_199293.3 | c.1309C>T | p.Arg437Trp | missense_variant | 13/14 | ||
TH | XM_011520335.3 | c.1240C>T | p.Arg414Trp | missense_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.1228C>T | p.Arg410Trp | missense_variant | 12/13 | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000225 AC: 56AN: 248838Hom.: 0 AF XY: 0.000193 AC XY: 26AN XY: 135040
GnomAD4 exome AF: 0.0000665 AC: 97AN: 1459588Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 52AN XY: 726116
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74444
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 441 of the TH protein (p.Arg441Trp). This variant is present in population databases (rs575326605, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of TH-related dystonia (PMID: 27619486; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 573670). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TH protein function. This variant disrupts the p.Arg441 amino acid residue in TH. Other variant(s) that disrupt this residue have been observed in individuals with TH-related conditions (PMID: 23939262, 27619486), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 06, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2021 | Variant summary: TH c.1321C>T (p.Arg441Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 248838 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TH causing Autosomal Recessive Segawa Syndrome, DOPA responsive dystonia phenotype (0.0011), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1321C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with DOPA responsive dystonia (Segawa Syndrome, Autosomal Recessive)(example, Yan_2017). Another individual with DOPA responsive dystonia and a compound heterozygous genotype including a different variant at the same codon, c.1322G>C (p.R441P) has also been reported (example, Haugarvoll_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. These data do not allow any conclusion about variant significance. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 26, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27619486) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at