rs786204540

Variant names:

• chr11-2165284-G-A
• rs786204540
• NM_000360.4:c.1282C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000360.4(TH):​c.1282C>T​(p.Gln428*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,460,580 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TH NM_000360.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.65

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2165284-G-A is Pathogenic according to our data. Variant chr11-2165284-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.1282C>T	p.Gln428*	stop_gained	Exon 12 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1375C>T	p.Gln459*	stop_gained	Exon 13 of 14		NP_954986.2
TH	NM_199293.3	c.1363C>T	p.Gln455*	stop_gained	Exon 13 of 14		NP_954987.2
TH	XM_011520335.3	c.1294C>T	p.Gln432*	stop_gained	Exon 12 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1282C>T	p.Gln428*	stop_gained	Exon 12 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460580 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726580

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:5

Jul 18, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 29, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TH c.1375C>T (p.Gln459X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250386 control chromosomes. c.1375C>T has been reported in the literature in at least one individual affected with tyrosine hydroxylase deficiency in the compound heterozygous state (Willemsen_2010). The variant was studied in vitro and was shown to have no measurable enzyme activity (Fossbakk_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln459*) in the TH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TH are known to be pathogenic (PMID: 22264700, 24753243). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with encephalopathy (PMID: 20430833). ClinVar contains an entry for this variant (Variation ID: 188890). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 08, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.95
GERP RS		2.4

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: rs786204540; hg19: chr11-2186514; COSMIC: COSV51747692; COSMIC: COSV51747692;