NM_000360.4(TH):c.934C>T (p.Gln312Ter) AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003474115.4

Allele description [Variation Report for NM_000360.4(TH):c.934C>T (p.Gln312Ter)]

NM_000360.4(TH):c.934C>T (p.Gln312Ter)

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.934C>T (p.Gln312Ter)

HGVS:

NC_000011.10:g.2166676G>A
NG_008128.1:g.10130C>T
NM_000360.4:c.934C>TMANE SELECT
NM_199292.2:c.1027C>T
NM_199292.3:c.1027C>T
NM_199293.3:c.1015C>T
NP_000351.2:p.Gln312Ter
NP_954986.2:p.Gln343Ter
NP_954987.2:p.Gln339Ter
NC_000011.9:g.2187906G>A

Protein change:

Q312*

Molecular consequence:

NM_000360.4:c.934C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_199292.3:c.1027C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_199293.3:c.1015C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004203854	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 4, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004547699	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22264700, 24753243, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004203854

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 4, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004547699

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 16, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Tyrosine hydroxylase deficiency in Taiwanese infants.

Chi CS, Lee HF, Tsai CR.

Pediatr Neurol. 2012 Feb;46(2):77-82. doi: 10.1016/j.pediatrneurol.2011.11.012.

PubMed [citation]

PMID:: 22264700

See all PubMed Citations (4)

Details of each submission

From Baylor Genetics, SCV004203854.2

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004547699.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with TH-related conditions. 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 sequence change creates a premature translational stop signal (p.Gln343*) in the TH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TH are known to be pathogenic (PMID: 22264700, 24753243).

#	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

Last Updated: Sep 29, 2024

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