11-2167445-T-G

Variant names:

• chr11-2167445-T-G
• rs778613708
• NM_000360.4:c.685A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000360.4(TH):​c.685A>C​(p.Ile229Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I229T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36802918).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.685A>C	p.Ile229Leu	missense	Exon 6 of 13	NP_000351.2
	TH	NM_199292.3		c.778A>C	p.Ile260Leu	missense	Exon 7 of 14	NP_954986.2
	TH	NM_199293.3		c.766A>C	p.Ile256Leu	missense	Exon 7 of 14	NP_954987.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.685A>C	p.Ile229Leu	missense	Exon 6 of 13	ENSP00000325951.4
	TH	ENST00000381178.5	TSL:1	c.778A>C	p.Ile260Leu	missense	Exon 7 of 14	ENSP00000370571.1
	TH	ENST00000381175.5	TSL:1	c.766A>C	p.Ile256Leu	missense	Exon 7 of 14	ENSP00000370567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Uncertain:1

Feb 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TH-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 260 of the TH protein (p.Ile260Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.37	T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.50		Loss of catalytic residue at I260 (P = 0.0441)
MVP		0.69
MPC		0.047
ClinPred		0.15	T
GERP RS		1.0
Varity_R		0.54
gMVP		0.60
Mutation Taster		=81/19	polymorphism

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: rs778613708; hg19: chr11-2188675;