NM_000360.4(TH):c.653C>T (p.Pro218Leu) AND Autosomal recessive DOPA responsive dystonia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 3, 2022
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:: RCV001833508.12

Allele description [Variation Report for NM_000360.4(TH):c.653C>T (p.Pro218Leu)]

NM_000360.4(TH):c.653C>T (p.Pro218Leu)

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.653C>T (p.Pro218Leu)

HGVS:

NC_000011.10:g.2167477G>A
NG_008128.1:g.9329C>T
NM_000360.4:c.653C>TMANE SELECT
NM_199292.3:c.746C>T
NM_199293.3:c.734C>T
NP_000351.2:p.Pro218Leu
NP_954986.2:p.Pro249Leu
NP_954987.2:p.Pro245Leu
NC_000011.9:g.2188707G>A
NM_199292.2:c.746C>T
p.PRO249LEU

Protein change:

P218L

Links:

dbSNP: rs377729019

NCBI 1000 Genomes Browser:

rs377729019

Molecular consequence:

NM_000360.4:c.653C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199292.3:c.746C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_199293.3:c.734C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002085321	Natera, Inc.	no assertion criteria provided	Uncertain significance (Mar 11, 2020)	germline	clinical testing
SCV002250166	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 10, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29801903, 28492532
SCV002790713	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 3, 2022)	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

SCV002085321

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Mar 11, 2020)

germline

clinical testing

SCV002250166

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 10, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002790713

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 3, 2022)

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

Targeted gene capture sequencing in diagnosis of dystonia patients.

Ma J, Wang L, Yang YM, Wan XH.

J Neurol Sci. 2018 Jul 15;390:36-41. doi: 10.1016/j.jns.2018.04.005. Epub 2018 Apr 6.

PubMed [citation]

PMID:: 29801903

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 (3)

Details of each submission

From Natera, Inc., SCV002085321.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002250166.2

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 249 of the TH protein (p.Pro249Leu). 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 generalized dystonia (PMID: 29801903). ClinVar contains an entry for this variant (Variation ID: 374731). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002790713.1

#	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: Nov 24, 2024

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