11-2167905-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000360.4(TH):c.605G>A(p.Arg202His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,610,938 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 Pathogenic (★★).
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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TH | NM_000360.4 | c.605G>A | p.Arg202His | missense_variant | Exon 5 of 13 | ENST00000352909.8 | NP_000351.2 | |
TH | NM_199292.3 | c.698G>A | p.Arg233His | missense_variant | Exon 6 of 14 | NP_954986.2 | ||
TH | NM_199293.3 | c.686G>A | p.Arg229His | missense_variant | Exon 6 of 14 | NP_954987.2 | ||
TH | XM_011520335.3 | c.617G>A | p.Arg206His | missense_variant | Exon 5 of 13 | XP_011518637.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000106 AC: 26AN: 244584Hom.: 0 AF XY: 0.0000903 AC XY: 12AN XY: 132926
GnomAD4 exome AF: 0.000145 AC: 211AN: 1458642Hom.: 0 Cov.: 33 AF XY: 0.000146 AC XY: 106AN XY: 725420
GnomAD4 genome AF: 0.000138 AC: 21AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74478
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Pathogenic:15Other:1
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The TH c.605G>A (p.Arg202His) missense variant, also referred to as p.Arg233His, has been reported in at least five studies in which it is reported in eight homozygotes, including two siblings (van den Heuvel et al. 1998; Najmabadi et al. 2011; Tan et al. 2014; Molero-Luis et al. 2013). Phenotypes of the individuals carrying the variant include L-DOPA-responsive dystonia (DRD), intellectual disability, unexplained dystonia without intellectual disability, and neurological disorders (van den Heuvel et al. 1998; Najmabadi et al. 2011; Tan et al. 2014; Molero-Luis et al. 2013). One homozygote with autosomal recessive intellectual disability identified in Najmabadi et al. (2011), also carried homozygous variants in seven other genes. The p.Arg202His variant was absent from 350 controls and is reported at a frequency of 0.000374 in the East Asian population of the Genome Aggregation Database. Fossbakk et al. (2014) performed thermal and kinetic analysis in E. coli and found that thermal stability was slightly reduced and residual activity of the variant protein was 14% of wild type. Based on the evidence, the p.Arg202His variant is classified as pathogenic for tyrosine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
NM_199292.2(TH):c.698G>A(R233H) is classified as pathogenic in the context of tyrosine hydroxylase deficiency. Sources cited for classification include the following: PMID 20430833, 9703425 and 24753243. Classification of NM_199292.2(TH):c.698G>A(R233H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
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Founder variant in Dutch population -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tyrosine hydroxylase-related neurological disorder (MIM#605407). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (32 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Biopterin_H domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is described as the most common allele causing Segawa syndrome (ClinVar, PMID: 27973928). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3. The variant was detected in compound heterozygous state with the variant c.614T>C (p.Leu205Pro). -
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This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the TH protein (p.Arg233His). This variant is present in population databases (rs80338892, gnomAD 0.04%). This missense change has been observed in individual(s) with tyrosine hydroxylase (TH) deficiency (PMID: 9703425, 10407773, 20430833, 20823027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12327). 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) has been performed 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. Experimental studies have shown that this missense change affects TH function (PMID: 20492352, 24753243, 26276013). For these reasons, this variant has been classified as Pathogenic. -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3. -
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26276013, 24753243, PS3). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID:20823027, 20430833; 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001160, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3Cnet: 0.974, PP3). Patient is considered compatible with Segawa syndrome, recessive (PP4_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:3
TH: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
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Functional studies indicate that R233H causes altered substrate specificity of the TH enzyme (Fossbakk et al., 2014); 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: 29126763, 16376043, 21937992, 9703425, 24753243, 26953246, 27973928, 25224241, 18554280, 22264700, 28667724, 28087438, 29961769, 10407773, 20430833, 30383639, 32872068, 31980526, 31589614, 33233562) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at