rs121917763

Positions:

chr11-2167896-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000360.4(TH):c.614T>C(p.Leu205Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,598 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: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: -0.400

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:

TH (HGNC:):

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, 0.97

PP5

Variant 11-2167896-A-G is Pathogenic according to our data. Variant chr11-2167896-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2167896-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4 linkuse as main transcript	c.614T>C	p.Leu205Pro	missense_variant	5/13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 linkuse as main transcript	c.707T>C	p.Leu236Pro	missense_variant	6/14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 linkuse as main transcript	c.695T>C	p.Leu232Pro	missense_variant	6/14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 linkuse as main transcript	c.626T>C	p.Leu209Pro	missense_variant	5/13		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.614T>C	p.Leu205Pro	missense_variant	5/13	1	NM_000360.4	ENSP00000325951.4		P07101-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

244378

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1458426

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Pathogenic:9Other:1

not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Greek population -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory Cellgenetics, GMDL Cellgenetics	-	The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in compound heterozygous state with c.605G>A (p.Arg202His). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 20, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 04, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jul 01, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in homozygous state. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 236 of the TH protein (p.Leu236Pro). This variant is present in population databases (rs121917763, gnomAD 0.003%). This missense change has been observed in individual(s) with tyrosine hydroxylase deficiency (PMID: 2019643, 8817341, 12891655, 19282209, 20430833, 23480488, 24753243; Invitae). 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.614T>C (p.Leu205Pro). ClinVar contains an entry for this variant (Variation ID: 12325). 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: 8817341). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2024	Published functional studies demonstrate a damaging effect, such that the mutant enzyme shows reduced activity compared to wild-type (PMID: 24753243, 8817341); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8817341, 23480488, 34426522, 38084654, 24753243) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TH: PM2, PM3, PS3:Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.061

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

0.34

N;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

N;N;.;N

REVEL

Uncertain

0.62

Sift

Benign

0.13

T;T;.;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.71

P;P;.;P

Vest4

0.74

MutPred

0.85

Loss of stability (P = 0.0158);.;.;.;

MVP

0.85

MPC

0.25

ClinPred

0.35

GERP RS

0.70

Varity_R

0.55

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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