NM_000360.4(TH):c.917G>A (p.Arg306His) AND Autosomal recessive DOPA responsive dystonia

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Oct 17, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000013121.22

Allele description

NM_000360.4(TH):c.917G>A (p.Arg306His)

Gene:

TH:tyrosine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000360.4(TH):c.917G>A (p.Arg306His)

HGVS:

NC_000011.10:g.2166693C>T
NG_008128.1:g.10113G>A
NM_000360.4:c.917G>AMANE SELECT
NM_199292.3:c.1010G>A
NM_199293.3:c.998G>A
NP_000351.2:p.Arg306His
NP_954986.2:p.Arg337His
NP_954987.2:p.Arg333His
NC_000011.9:g.2187923C>T
NM_199292.2:c.1010G>A
P07101:p.Arg337His

Protein change:

R306H; ARG337HIS

Links:

UniProtKB: P07101#VAR_014030; OMIM: 191290.0004; dbSNP: rs28934580

NCBI 1000 Genomes Browser:

rs28934580

Molecular consequence:

NM_000360.4:c.917G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199292.3:c.1010G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199293.3:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal recessive DOPA responsive dystonia
Synonyms:: Segawa syndrome, autosomal recessive; DYT-TH; TH-deficient dopa-responsive dystonia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011551; MedGen: C2673535; Orphanet: 101150; OMIM: 605407

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033368	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2000)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000800575	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Aug 11, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11246459, 15468323 Citation Link,
SCV002238974	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11246459, 15468323, 24753243, 28492532
SCV004203870	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 25, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism.

Swaans RJ, Rondot P, Renier WO, Van Den Heuvel LP, Steenbergen-Spanjers GC, Wevers RA.

Ann Hum Genet. 2000 Jan;64(Pt 1):25-31. doi: 10.1017/S0003480000007922.

PubMed [citation]

PMID:: 11246459

Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein.

Royo M, Daubner SC, Fitzpatrick PF.

Proteins. 2005 Jan 1;58(1):14-21.

PubMed [citation]

PMID:: 15468323
PMCID:: PMC1945158

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000033368.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Swaans et al. (2000) described compound heterozygosity for 2 mutations in the TH gene as the basis of infantile parkinsonism (605407) in 2 brothers: 1010G-A (arg337 to his) and a 1481C-T (thr494 to met; 191290.0005). The disease began with gait disturbance at the age of 2 years in one brother, and with a tremor of the hand at the age of 5 years in the other. The motor disturbance spread to the limbs, preventing all voluntary movements for the first brother. At the age of 5 years he was no longer able to walk. In his older brother, severe lordosis developed as well as an extension attitude of the lower limbs hindering gait. By the age of 9 years he could no longer walk. After 1 month of low-dose L-DOPA treatment in combination with carbidopa, motor performance normalized for both patients. Thirty years later the treatment was still continued without fluctuation of efficacy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000800575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002238974.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 337 of the TH protein (p.Arg337His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile parkinsonism (PMID: 11246459). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as R306H. ClinVar contains an entry for this variant (Variation ID: 12328). 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: 15468323, 24753243). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004203870.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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