rs771351747

chr11-2164327-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_000360.4(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 NM_000360.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.94

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]

ACMG classification

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 NM_000360.4
• 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, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TH	NM_000360.4	c.1400A>G	p.Asp467Gly	missense_variant	13/13	ENST00000352909.8
TH	NM_199292.3	c.1493A>G	p.Asp498Gly	missense_variant	14/14
TH	NM_199293.3	c.1481A>G	p.Asp494Gly	missense_variant	14/14
TH	XM_011520335.3	c.1412A>G	p.Asp471Gly	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TH	ENST00000352909.8	c.1400A>G	p.Asp467Gly	missense_variant	13/13	1	NM_000360.4	P1
TH	ENST00000381178.5	c.1493A>G	p.Asp498Gly	missense_variant	14/14	1
TH	ENST00000381175.5	c.1481A>G	p.Asp494Gly	missense_variant	14/14	1
TH	ENST00000333684.9	c.1118A>G	p.Asp373Gly	missense_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152112 Hom.: 0 Cov.: 33

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: 11 AN: 199036 Hom.: 0 AF XY: 0.0000464 AC XY: 5 AN XY: 107782

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: 81 AN: 1387894 Hom.: 0 Cov.: 31 AF XY: 0.0000717 AC XY: 49 AN XY: 683466

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: 4 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

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.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000745 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.0	M;.;.;.
MutationTaster	Benign	0.89	D;D;D;N
PrimateAI	Uncertain	0.57	T
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	D
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

Other links and lift over

dbSNP: rs771351747; hg19: chr11-2185557;