NM_000360.4(TH):c.711del (p.Thr238fs) AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 19, 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:: RCV003625595.3

Allele description [Variation Report for NM_000360.4(TH):c.711del (p.Thr238fs)]

NM_000360.4(TH):c.711del (p.Thr238fs)

Gene:

TH:tyrosine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000360.4(TH):c.711del (p.Thr238fs)

HGVS:

NC_000011.10:g.2167018del
NG_008128.1:g.9789del
NM_000360.4:c.711delMANE SELECT
NM_199292.2:c.804del
NM_199292.3:c.804del
NM_199293.3:c.792del
NP_000351.2:p.Thr238fs
NP_954986.2:p.Thr269fs
NP_954987.2:p.Thr265fs
NC_000011.9:g.2188247del
NC_000011.9:g.2188248del

Protein change:

T238fs

Molecular consequence:

NM_000360.4:c.711del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199292.3:c.804del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199293.3:c.792del - 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
SCV004430799	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22264700, 24753243, 28492532
SCV005054282	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 19, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004430799

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 9, 2023)

germline

clinical testing

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

SCV005054282

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 19, 2024)

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

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004430799.1

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

Description

This variant has not been reported in the literature in individuals affected with TH-related conditions. This sequence change creates a premature translational stop signal (p.Thr269Argfs*2) 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). This variant is not present in population databases (gnomAD no frequency). 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, SCV005054282.1

#	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: Sep 29, 2024

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