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

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 2.96
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a helix (size 5) in uniprot entity TY3H_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000360.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 11-2167905-C-T is Pathogenic according to our data. Variant chr11-2167905-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2167905-C-T is described in Lovd as [Pathogenic]. Variant chr11-2167905-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
THNM_000360.4 linkc.605G>A p.Arg202His missense_variant Exon 5 of 13 ENST00000352909.8 NP_000351.2 P07101-3
THNM_199292.3 linkc.698G>A p.Arg233His missense_variant Exon 6 of 14 NP_954986.2 P07101-1P78428
THNM_199293.3 linkc.686G>A p.Arg229His missense_variant Exon 6 of 14 NP_954987.2 P07101-2P78428
THXM_011520335.3 linkc.617G>A p.Arg206His missense_variant Exon 5 of 13 XP_011518637.1 P07101-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
THENST00000352909.8 linkc.605G>A p.Arg202His missense_variant Exon 5 of 13 1 NM_000360.4 ENSP00000325951.4 P07101-3

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000106
AC:
26
AN:
244584
Hom.:
0
AF XY:
0.0000903
AC XY:
12
AN XY:
132926
show subpopulations
Gnomad AFR exome
AF:
0.0000644
Gnomad AMR exome
AF:
0.0000585
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000329
Gnomad SAS exome
AF:
0.0000665
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000127
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.000145
AC:
211
AN:
1458642
Hom.:
0
Cov.:
33
AF XY:
0.000146
AC XY:
106
AN XY:
725420
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000898
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.0000816
Gnomad4 FIN exome
AF:
0.0000384
Gnomad4 NFE exome
AF:
0.000165
Gnomad4 OTH exome
AF:
0.0000996
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000162
Hom.:
0
Bravo
AF:
0.0000869
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000107
AC:
13

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:15Other:1
Jul 30, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 14, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 19, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 08, 2022
Center for Molecular Medicine, Children’s Hospital of Fudan University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 07, 2017
SingHealth Duke-NUS Institute of Precision Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Founder variant in Dutch population -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 16, 2018
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory Cellgenetics, GMDL Cellgenetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

Jan 10, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 27, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 12, 2020
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3. -

Oct 02, 2021
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TH: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Nov 22, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 29, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;.;.;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.9
H;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.7
D;D;.;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.94
MVP
0.98
MPC
0.35
ClinPred
0.54
D
GERP RS
3.1
Varity_R
0.89
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80338892; hg19: chr11-2189135; COSMIC: COSV60768681; COSMIC: COSV60768681; API