NM_000360.4(TH):c.1282C>T (p.Gln428Ter) AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Feb 8, 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:: RCV000169247.9

Allele description [Variation Report for NM_000360.4(TH):c.1282C>T (p.Gln428Ter)]

NM_000360.4(TH):c.1282C>T (p.Gln428Ter)

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.1282C>T (p.Gln428Ter)

HGVS:

NC_000011.10:g.2165284G>A
NG_007114.1:g.911C>T
NG_008128.1:g.11522C>T
NG_050578.1:g.926C>T
NM_000360.4:c.1282C>TMANE SELECT
NM_199292.3:c.1375C>T
NM_199293.3:c.1363C>T
NP_000351.2:p.Gln428Ter
NP_954986.2:p.Gln459Ter
NP_954987.2:p.Gln455Ter
NC_000011.9:g.2186514G>A
NM_000360.3:c.1282C>T
NM_199292.2:c.1375C>T

Protein change:

Q428*

Links:

dbSNP: rs786204540

NCBI 1000 Genomes Browser:

rs786204540

Molecular consequence:

NM_000360.4:c.1282C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_199292.3:c.1375C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_199293.3:c.1363C>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
SCV000220529	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 18, 2014)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 24753243, 20430833 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001584620	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22264700, 24753243, 20430833, 28492532
SCV002556256	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 29, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24753243, 20430833 Citation Link,
SCV005051983	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV005054284	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
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, literature only

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000220529.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001584620.4

#	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 creates a premature translational stop signal (p.Gln459*) 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). This premature translational stop signal has been observed in individual(s) with encephalopathy (PMID: 20430833). ClinVar contains an entry for this variant (Variation ID: 188890). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002556256.1

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

Description

Variant summary: TH c.1375C>T (p.Gln459X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250386 control chromosomes. c.1375C>T has been reported in the literature in at least one individual affected with tyrosine hydroxylase deficiency in the compound heterozygous state (Willemsen_2010). The variant was studied in vitro and was shown to have no measurable enzyme activity (Fossbakk_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051983.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV005054284.1

#	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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