rs121917765

Positions:

• chr11-2166544-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000360.4(TH):​c.983G>T​(p.Cys328Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,594 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: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.41

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 11-2166544-C-A is Pathogenic according to our data. Variant chr11-2166544-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12334.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4	c.983G>T	p.Cys328Phe	missense_variant	9/13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1076G>T	p.Cys359Phe	missense_variant	10/14		NP_954986.2
TH	NM_199293.3	c.1064G>T	p.Cys355Phe	missense_variant	10/14		NP_954987.2
TH	XM_011520335.3	c.995G>T	p.Cys332Phe	missense_variant	9/13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.983G>T	p.Cys328Phe	missense_variant	9/13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449594 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720526

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: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2022	Variant summary: TH c.1076G>T (p.Cys359Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 217992 control chromosomes. c.1076G>T has been reported in the literature as a homozygous genotype in at-least one individual affected with Tyrosine Hydroxylase Deficiency and continues to be reported/cited by others (example, Brautigam_1999, Dionisi-Vici_2000, Hoffmann_2003, Dong_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Fossbakk_2014). The most pronounced variant effect results in severely reduced activity compared with wt TH ( 10%), and significantly altered affinities for both tyrosine and the cofactor BH4. Interestingly, this mutation led to a higher selectivity for L-Tyrosine. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.8	D;D;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.86
MutPred		0.73		Gain of glycosylation at P355 (P = 0.2038);.;.;.;
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.98
gMVP		0.96

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: rs121917765; hg19: chr11-2187774;