11-2164327-T-C

Position:

chr11-2164327-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The ENST00000352909.8(TH):c.1400A>G(p.Asp467Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000552 in 1,540,006 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D467E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

TH
ENST00000352909.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.94

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000352909.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2164328-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1347919.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

PP5

Variant 11-2164327-T-C is Pathogenic according to our data. Variant chr11-2164327-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304067.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4 linkuse as main transcript	c.1400A>G	p.Asp467Gly	missense_variant	13/13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 linkuse as main transcript	c.1493A>G	p.Asp498Gly	missense_variant	14/14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 linkuse as main transcript	c.1481A>G	p.Asp494Gly	missense_variant	14/14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 linkuse as main transcript	c.1412A>G	p.Asp471Gly	missense_variant	13/13		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.1400A>G	p.Asp467Gly	missense_variant	13/13	1	NM_000360.4	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5 linkuse as main transcript	c.1493A>G	p.Asp498Gly	missense_variant	14/14	1		ENSP00000370571.1	P07101-1
TH	ENST00000381175.5 linkuse as main transcript	c.1481A>G	p.Asp494Gly	missense_variant	14/14	1		ENSP00000370567.1	P07101-2
TH	ENST00000333684.9 linkuse as main transcript	c.1118A>G	p.Asp373Gly	missense_variant	11/11	1		ENSP00000328814.6	P07101-6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000553

AC:

AN:

199036

Hom.:

AF XY:

0.0000464

AC XY:

AN XY:

107782

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:

0.000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000584

AC:

AN:

1387894

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

683466

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:

0.0000737

Gnomad4 OTH exome

AF:

0.0000350

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TH c.1400A>G (p.Asp467Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state in three patients (including two brothers) with dopa-responsive dystonia (Furukawa et al. 2001; Schiller et al. 2004). The variant was found in a heterozygous state in two unaffected parents. The variant has also been reported in a heterozygous state in one patient with Parkinson disease (Rengmark et al. 2016). The p.Asp467Gly variant was absent from 230 controls and is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Asp467 residue is conserved and located in the tetramerization domain suggesting that the variant may exert a significant influence on oligomerization of the protein. In a study in E. Coli, the presence of the p.Asp467Gly variant resulted in a significant reduction in protein levels with less than 10% residual activity compared to wild type protein (Fossbakk et al. 2014). Based on the evidence the p.Asp467Gly variant is classified as a variant of unknown significance but suspicious for pathogenicity 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	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 498 of the TH protein (p.Asp498Gly). This variant is present in population databases (rs771351747, gnomAD 0.01%). This missense change has been observed in individual(s) with TH-related conditions and L-dopa responsive dystonia (PMID: 11160968, 15505183, 15747353). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 304067). 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: 24753243). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

0.89

D;D;D;N

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

D;D;.;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0030

D;D;.;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.94

P;P;.;P

Vest4

0.17

MVP

0.99

MPC

1.5

ClinPred

0.81

GERP RS

3.1

Varity_R

0.69

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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