ClinVar Genomic variation as it relates to human health
NM_000360.4(TH):c.1388C>T (p.Thr463Met)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000360.4(TH):c.1388C>T (p.Thr463Met)
Variation ID: 12326 Accession: VCV000012326.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 2164339 (GRCh38) [ NCBI UCSC ] 11: 2185569 (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 Jul 25, 2015 Feb 14, 2024 Oct 25, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000360.4:c.1388C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000351.2:p.Thr463Met missense NM_199292.3:c.1481C>T NP_954986.2:p.Thr494Met missense NM_199293.3:c.1469C>T NP_954987.2:p.Thr490Met missense NC_000011.10:g.2164339G>A NC_000011.9:g.2185569G>A NG_007114.1:g.1856C>T NG_008128.1:g.12467C>T NG_050578.1:g.1871C>T P07101:p.Thr494Met - Protein change
- T494M, T463M, T490M
- Other names
- -
- Canonical SPDI
- NC_000011.10:2164338: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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
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 |
1091 | 1142 |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 25, 2023 | RCV000013119.23 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 19, 2018 | RCV000622283.3 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002243234.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 494 of the TH protein (p.Thr494Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 494 of the TH protein (p.Thr494Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of tyrosine hydroxylase deficiency (PMID: 11246459, 29225908; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as T463M. ClinVar contains an entry for this variant (Variation ID: 12326). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TH protein function. Experimental studies have shown that this missense change affects TH function (PMID: 15468323). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Uncertain significance
(Jan 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741297.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Hispanic/Portuguese/Spanish/Aztec Indian
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV004013579.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Functional studies provide strong evidence of the … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15468323). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.52). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012326 / PMID: 11246459). The variant was reported homozygous in an affected patient (PMID: 29225908). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Spasticity (present) , Dystonic disorder (present) , Language disorder (present)
|
|
Likely pathogenic
(Oct 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive DOPA responsive dystonia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203835.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 01, 2000)
|
no assertion criteria provided
Method: literature only
|
SEGAWA SYNDROME, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033366.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 20, 2021 |
Comment on evidence:
For discussion of the thr494-to-met (T494M) mutation in the TH gene that was found in compound heterozygous state in 2 sibs with infantile parkinsonism (605407) … (more)
For discussion of the thr494-to-met (T494M) mutation in the TH gene that was found in compound heterozygous state in 2 sibs with infantile parkinsonism (605407) by Swaans et al. (2000), see 191290.0004. (less)
|
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 |
---|---|---|---|---|
An unusual presentation of tyrosine hydroxylase deficiency. | Katus LE | Journal of clinical movement disorders | 2017 | PMID: 29225908 |
Effects of mutations in tyrosine hydroxylase associated with progressive dystonia on the activity and stability of the protein. | Royo M | Proteins | 2005 | PMID: 15468323 |
Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism. | Swaans RJ | Annals of human genetics | 2000 | PMID: 11246459 |
Text-mined citations for rs45471299 ...
HelpRecord last updated May 19, 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.