rs767635052

Variant names:

• chr11-2164345-G-A
• rs767635052
• NM_000360.4:c.1382C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2164345-G-A
• chr11-2164345-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000360.4(TH):​c.1382C>T​(p.Pro461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000175 in 1,546,302 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P461R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 6.70
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000360.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-2164345-G-A is Pathogenic according to our data. Variant chr11-2164345-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1004173.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.1382C>T	p.Pro461Leu	missense_variant	Exon 13 of 13	ENST00000352909.8	NP_000351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1382C>T	p.Pro461Leu	missense_variant	Exon 13 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD2 exomes AF: 0.0000147 AC: 3 AN: 203614 AF XY: 0.00000903

Gnomad AFR exome AF: 0.0000729

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 21 AN: 1394106 Hom.: 0 Cov.: 31 AF XY: 0.00000727 AC XY: 5 AN XY: 687792

African (AFR) AF: 0.0000985 AC: 3 AN: 30446

American (AMR) AF: 0.00 AC: 0 AN: 37024

Ashkenazi Jewish (ASJ) AF: 0.0000432 AC: 1 AN: 23156

East Asian (EAS) AF: 0.00 AC: 0 AN: 36392

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1075274

Other (OTH) AF: 0.0000174 AC: 1 AN: 57388

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:5 Uncertain:1

Feb 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 492 of the TH protein (p.Pro492Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of TH-related conditions (PMID: 17696123, 20430833; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1004173). 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). This variant disrupts the p.Pro492 amino acid residue in TH. Other variant(s) that disrupt this residue have been observed in individuals with TH-related conditions (PMID: 20399390), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Feb 12, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_199292.2(TH):c.1475C>T(P492L) is a missense variant classified as likely pathogenic in the context of tyrosine hydroxylase deficiency. P492L has been observed in cases with relevant disease (PMID: 20430833, 17696123, 31273557, 33742171). Functional assessments of this variant are available in the literature (PMID: 24753243). P492L has been observed in population frequency databases (gnomAD AFR 0.01%). In summary, NM_199292.2(TH):c.1475C>T(P492L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Feb 17, 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.1475C>T (p.Pro492Leu) results in a non-conservative amino acid change located in the catalytic domain (IPR041903) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.5e-05 in 203614 control chromosomes (gnomAD). The variant, c.1475C>T, has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with tyrosine hydroxylase (TH) deficiency or TH deficiency related clinical symptoms (Verbeek_2007, Willemsen_2010, Monies_2019, Ali_2020, Sallevelt_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had no measurable enzyme activity in a bacterial expression system (Fossbakk_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and one laboratory classified the variant as likely pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.0	D;D;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.87
MutPred		0.88		Loss of methylation at K489 (P = 0.1018);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.89
gMVP		0.81
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs767635052; hg19: chr11-2185575; COSMIC: COSV99048104; COSMIC: COSV99048104;