11-2167905-C-T

Position:

• chr11-2167905-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 2.96

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.605G>A	p.Arg202His	missense_variant	5/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.698G>A	p.Arg233His	missense_variant	6/14		NP_954986.2
TH	NM_199293.3	c.686G>A	p.Arg229His	missense_variant	6/14		NP_954987.2
TH	XM_011520335.3	c.617G>A	p.Arg206His	missense_variant	5/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.605G>A	p.Arg202His	missense_variant	5/13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152178 Hom.: 0 Cov.: 33

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

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

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

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:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:15 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 16, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Dutch population -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 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). 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. 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	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). -
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	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	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	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. -
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, criteria provided, single submitter	clinical testing	3billion	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, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

not provided Pathogenic:3

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

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

Other links and lift over

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