NM_000360.4(TH):c.90+13G>T AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 12, 2024
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:: RCV000670358.9

Allele description [Variation Report for NM_000360.4(TH):c.90+13G>T]

NM_000360.4(TH):c.90+13G>T

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.90+13G>T

HGVS:

NC_000011.10:g.2171684C>A
NG_008128.1:g.5122G>T
NM_000360.4:c.90+13G>TMANE SELECT
NM_199292.3:c.102+1G>T
NM_199293.3:c.90+13G>T
NC_000011.9:g.2192914C>A
NM_199292.2:c.102+1G>T

Links:

dbSNP: rs77140743

NCBI 1000 Genomes Browser:

rs77140743

Molecular consequence:

NM_000360.4:c.90+13G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_199293.3:c.90+13G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_199292.3:c.102+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000795200	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Oct 31, 2017)	unknown	clinical testing	Citation Link,
SCV002297812	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 2, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 22264700, 24753243, 28492532
SCV004203875	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 12, 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

SCV000795200

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Oct 31, 2017)

unknown

clinical testing

Citation Link,

SCV002297812

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 2, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004203875

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 12, 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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

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 (5)

Details of each submission

From Counsyl, SCV000795200.1

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

#	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, SCV002297812.3

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 554683). 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 affects a donor splice site in intron 1 of the TH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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

From Baylor Genetics, SCV004203875.2

#	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

Last Updated: Jun 17, 2024

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