NM_000360.4(TH):c.739_743dup (p.Cys248fs) AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 23, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003032358.3

Allele description [Variation Report for NM_000360.4(TH):c.739_743dup (p.Cys248fs)]

NM_000360.4(TH):c.739_743dup (p.Cys248fs)

Gene:

TH:tyrosine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000360.4(TH):c.739_743dup (p.Cys248fs)

HGVS:

NC_000011.10:g.2166985_2166989dup
NG_008128.1:g.9817_9821dup
NM_000360.4:c.739_743dupMANE SELECT
NM_199292.3:c.832_836dup
NM_199293.3:c.820_824dup
NP_000351.2:p.Cys248fs
NP_954986.2:p.Cys279fs
NP_954987.2:p.Cys275fs
NC_000011.9:g.2188214_2188215insCAGGC
NC_000011.9:g.2188215_2188219dup

Protein change:

C248fs

Molecular consequence:

NM_000360.4:c.739_743dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199292.3:c.832_836dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199293.3:c.820_824dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV003336914	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2022)	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

SCV003336914

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2022)

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

Citations

PubMed

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

Functional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in Dopa-responsive dystonia.

Fossbakk A, Kleppe R, Knappskog PM, Martinez A, Haavik J.

Hum Mutat. 2014 Jul;35(7):880-90. doi: 10.1002/humu.22565. Epub 2014 Jun 3.

PubMed [citation]

PMID:: 24753243
PMCID:: PMC4312968

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003336914.2

#	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. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys279Trpfs*34) 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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