rs575326605
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
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).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
TH
NM_000360.4 missense
NM_000360.4 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 0.351
Genes affected
TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-2165338-G-A is Pathogenic according to our data. Variant chr11-2165338-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573670.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_pathogenic=4}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TH | NM_000360.4 | c.1228C>T | p.Arg410Trp | missense_variant | Exon 12 of 13 | ENST00000352909.8 | NP_000351.2 | |
| TH | NM_199292.3 | c.1321C>T | p.Arg441Trp | missense_variant | Exon 13 of 14 | NP_954986.2 | ||
| TH | NM_199293.3 | c.1309C>T | p.Arg437Trp | missense_variant | Exon 13 of 14 | NP_954987.2 | ||
| TH | XM_011520335.3 | c.1240C>T | p.Arg414Trp | missense_variant | Exon 12 of 13 | XP_011518637.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000225 AC: 56AN: 248838Hom.: 0 AF XY: 0.000193 AC XY: 26AN XY: 135040
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GnomAD4 exome AF: 0.0000665 AC: 97AN: 1459588Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 52AN XY: 726116
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GnomAD4 genome 0.0000263 AC: 4AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Pathogenic:5Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed missense c.1228C>T(p.Arg410Trp) / c.1321C>T (p.Arg441Trp) variant in TH gene has been reported previously in individual(s) affected with TH associated Segawa Syndrome (Yan YP, et al., 2017). The p.Arg410Trp variant has been reported with allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Uncertain Significance (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on TH gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 410 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [c.1322G>C (p.Arg441Pro] on the same residue of this gene has previously been reported to be disease causing (Haugarvoll K & Bindoff LA., 2011), suggesting that this residue might be of clinical significance. For these reasons, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 23, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2025 | 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, 37840187; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1228C>T . ClinVar contains an entry for this variant (Variation ID: 573670). 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 TH protein function with a positive predictive value of 80%. 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 | - - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 30, 2024 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. This variant segregates with disease in at least one family. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. - |
| 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) - |
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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;D
Vest4
MutPred
Loss of disorder (P = 0.0143);.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at