11-2167905-C-T

Variant names:

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

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]

TH links:

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
TH	NM_000360.4 link	c.605G>A	p.Arg202His	missense_variant	Exon 5 of 13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 link	c.698G>A	p.Arg233His	missense_variant	Exon 6 of 14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 link	c.686G>A	p.Arg229His	missense_variant	Exon 6 of 14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 link	c.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
TH	ENST00000352909.8 link	c.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:

AN:

152178

Hom.:

Cov.:

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:

AN:

244584

Hom.:

AF XY:

0.0000903

AC XY:

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.:

Cov.:

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

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.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

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

Pathogenic, no assertion criteria provided	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Feb 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	Oct 02, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 12, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	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. -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Dutch population -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory Cellgenetics, GMDL Cellgenetics	-	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). -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TH: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.9

H;.;.;.

PrimateAI

Uncertain

0.61

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over