Genetic Variant TH:p.Val468Leu (chr11-2164325-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000360.4(TH):c.1402G>C(p.Val468Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V468M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.22

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

TH-deficient dopa-responsive dystonia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
tyrosine hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

TH links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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, 12 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 chr11-2164325-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412030.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	NM_000360.4	MANE Select	c.1402G>C	p.Val468Leu	missense	Exon 13 of 13	NP_000351.2	P07101-3
TH	NM_199292.3		c.1495G>C	p.Val499Leu	missense	Exon 14 of 14	NP_954986.2	P07101-1
TH	NM_199293.3		c.1483G>C	p.Val495Leu	missense	Exon 14 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TH	ENST00000352909.8	TSL:1 MANE Select	c.1402G>C	p.Val468Leu	missense	Exon 13 of 13	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5	TSL:1	c.1495G>C	p.Val499Leu	missense	Exon 14 of 14	ENSP00000370571.1	P07101-1
TH	ENST00000381175.5	TSL:1	c.1483G>C	p.Val495Leu	missense	Exon 14 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.68

MetaRNN

Uncertain

0.57

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

PhyloP100

4.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.43

Sift

Benign

0.090

Sift4G

Benign

0.10

Polyphen

0.30

Vest4

0.11

MutPred

0.57

Loss of sheet (P = 0.1398)

MVP

0.90

MPC

0.73

ClinPred

0.76

GERP RS

3.4

Varity_R

0.26

gMVP

0.53

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over