11-2166941-C-G

Variant names:

• chr11-2166941-C-G
• rs755536257
• NM_000360.4:c.787G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000360.4(TH):​c.787G>C​(p.Gly263Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,446,448 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G263S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 5.74
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 11-2166941-C-G is Pathogenic according to our data. Variant chr11-2166941-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551155.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.787G>C	p.Gly263Arg	missense_variant	Exon 7 of 13	ENST00000352909.8	NP_000351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.787G>C	p.Gly263Arg	missense_variant	Exon 7 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000182 AC: 4 AN: 220078 AF XY: 0.0000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1446448 Hom.: 0 Cov.: 64 AF XY: 0.00000279 AC XY: 2 AN XY: 718060

African (AFR) AF: 0.00 AC: 0 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 42782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.0000768 AC: 3 AN: 39082

South Asian (SAS) AF: 0.00 AC: 0 AN: 83536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105750

Other (OTH) AF: 0.00 AC: 0 AN: 59802

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000286 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:1 Uncertain:2

Nov 30, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 28, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 19, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20056467, 20823027, 32959227) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.050	T;D;T
Polyphen		1.0	D;D;D
Vest4		0.86
MutPred		0.89		Gain of solvent accessibility (P = 0.019);.;.;
MVP		0.98
MPC		0.34
ClinPred		0.93	D
GERP RS		3.3
Varity_R		0.90
gMVP		0.90
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs755536257; hg19: chr11-2188171;