ClinVar Genomic variation as it relates to human health
NM_199292.3(TH):c.-71C>T
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_199292.3(TH):c.-71C>T
Variation ID: 558656 Accession: VCV000558656.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 2171857 (GRCh38) [ NCBI UCSC ] 11: 2193087 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 5, 2018 Mar 5, 2024 Jan 2, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_199292.3:c.-71C>T NC_000011.10:g.2171857G>A NC_000011.9:g.2193087G>A NG_008128.1:g.4949C>T - Protein change
- Other names
- -
- Canonical SPDI
- NC_000011.10:2171856:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
TH | - | - |
GRCh38 GRCh37 |
1088 | 1139 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2024 | RCV000674959.19 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jun 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800375.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
Pathogenic
(Aug 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004038530.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: TH c.-71C>T alters a conserved nucleotide located within the cAMP response element (CRE) in the untranscribed region upstream of the TH gene. The … (more)
Variant summary: TH c.-71C>T alters a conserved nucleotide located within the cAMP response element (CRE) in the untranscribed region upstream of the TH gene. The variant was absent in 31334 control chromosomes. c.-71C>T has been reported in the literature as homozygous or compound heterozygous genotypes in multiple individuals affected with Segawa Syndrome, Autosomal Recessive (DOPA-responsive dystonia) (example, Verbeek_2007, Ribases_2007, Stamelou_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a reduction of 90% of basal transcription of the TH promotor in-vitro (Tinti_1997). The following publications have been ascertained in the context of this evaluation (PMID: 32872068, 25910213, 17698383, 22815559, 17696123, 9235905). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Likely pathogenic
(Sep 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203853.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001213669.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This variant occurs in a non-coding region of the TH gene. It does not change the encoded amino acid sequence of the TH protein. This … (more)
This variant occurs in a non-coding region of the TH gene. It does not change the encoded amino acid sequence of the TH protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with TH-related conditions and dystonia (PMID: 17696123, 17698383, 22815559). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1-71 C>T. ClinVar contains an entry for this variant (Variation ID: 558656). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TH function (PMID: 9235905, 25910213). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: yes
Allele origin:
maternal
|
Molecular Genetics Lab, CHRU Brest
Accession: SCV004697602.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
Pathogenic
(Sep 15, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive Segawa syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002092217.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Dopa-responsive dystonia caused by tyrosine hydroxylase deficiency: Three cases report and literature review. | Dong HY | Medicine | 2020 | PMID: 32872068 |
Human gene-centered transcription factor networks for enhancers and disease variants. | Fuxman Bass JI | Cell | 2015 | PMID: 25910213 |
Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. | Stamelou M | Neurology | 2012 | PMID: 22815559 |
A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa-responsive encephalopathy: clinical, biochemical and genetic analysis. | Ribasés M | Molecular genetics and metabolism | 2007 | PMID: 17698383 |
Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. | Verbeek MM | Annals of neurology | 2007 | PMID: 17696123 |
Structure/function relationship of the cAMP response element in tyrosine hydroxylase gene transcription. | Tinti C | The Journal of biological chemistry | 1997 | PMID: 9235905 |
Text-mined citations for rs549435434 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.