rs1288483479
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000360.4(TH):c.850G>A(p.Gly284Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000787 in 1,396,830 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000079 ( 0 hom. )
Consequence
TH
NM_000360.4 missense
NM_000360.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 5.79
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 Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
?
Variant 11-2166760-C-T is Pathogenic according to our data. Variant chr11-2166760-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TH | NM_000360.4 | c.850G>A | p.Gly284Ser | missense_variant | 8/13 | ENST00000352909.8 | |
TH | NM_199292.3 | c.943G>A | p.Gly315Ser | missense_variant | 9/14 | ||
TH | NM_199293.3 | c.931G>A | p.Gly311Ser | missense_variant | 9/14 | ||
TH | XM_011520335.3 | c.862G>A | p.Gly288Ser | missense_variant | 8/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TH | ENST00000352909.8 | c.850G>A | p.Gly284Ser | missense_variant | 8/13 | 1 | NM_000360.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD3 exomes AF: 0.00000699 AC: 1AN: 143142Hom.: 0 AF XY: 0.0000129 AC XY: 1AN XY: 77636
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GnomAD4 exome AF: 0.00000787 AC: 11AN: 1396830Hom.: 0 Cov.: 64 AF XY: 0.00000726 AC XY: 5AN XY: 688896
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GnomAD4 genome ? Cov.: 34
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the TH protein (p.Gly315Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of tyrosine hydroxylase deficiency (PMID: 22264700, 25758715, 28087438, 32005694). 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: 558576). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 24, 2023 | Variant summary: TH c.943G>A (p.Gly315Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (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 7e-06 in 143142 control chromosomes (gnomAD). c.943G>A has been reported in the literature in multiple individuals with clinical features of tyrosine hydroxylase deficiency (example: Mak_2010, Chi_2012, Mercimek-Mahmutoglu_2015, Cordeiro_2018, and Dong_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22264700, 30109838, 32005694, 20056467, 25758715). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Gain of disorder (P = 0.0764);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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