NM_000161.3(GCH1):c.344-1G>A AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 24, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000634832.6

Allele description [Variation Report for NM_000161.3(GCH1):c.344-1G>A]

NM_000161.3(GCH1):c.344-1G>A

Gene:

GCH1:GTP cyclohydrolase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q22.2

Genomic location:

Preferred name:

NM_000161.3(GCH1):c.344-1G>A

HGVS:

NC_000014.9:g.54865437C>T
NG_008647.1:g.42388G>A
NG_008647.2:g.42389G>A
NM_000161.3:c.344-1G>AMANE SELECT
NM_001024024.2:c.344-1G>A
NM_001024070.2:c.344-1G>A
NM_001024071.2:c.344-1G>A
NC_000014.8:g.55332155C>T
NM_000161.2:c.344-1G>A

Links:

dbSNP: rs1555360050

NCBI 1000 Genomes Browser:

rs1555360050

Molecular consequence:

NM_000161.3:c.344-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001024024.2:c.344-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001024070.2:c.344-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001024071.2:c.344-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Dystonia 5 (DRD)
Synonyms:: Dystonia 5, Dopa-responsive type; Dystonia, progressive, with diurnal variation; Dystonia-Parkinsonism with diurnal fluctuation; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007495; MedGen: C1851920; Orphanet: 98808; OMIM: 128230

Name:: GTP cyclohydrolase I deficiency
Identifiers:: MONDO: MONDO:0100184; MedGen: C0268467

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000756176	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 24, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 19491146, 8619546, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000756176

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 24, 2017)

germline

clinical testing

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

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

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

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia.

Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, Landrieu P, Nguyen K, Ponsot G, Abada M, Doummar D, Damier P, Gil R, Thobois S, Ward AJ, Hutchinson M, Toutain A, Picard F, Camuzat A, Fedirko E, Sân C, Bouteiller D, et al.

Brain. 2009 Jul;132(Pt 7):1753-63. doi: 10.1093/brain/awp084. Epub 2009 Jun 2.

PubMed [citation]

PMID:: 19491146

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000756176.4

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

Description

This variant has been reported in individuals affected with dystonia (PMID: 8619546, Invitae). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GCH1 are known to be pathogenic (PMID: 19491146). Experimental studies have shown that this acceptor splice site variant leads to skipping of exon 2 and reduced mRNA expresssion (PMID: 8619546). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 1 of the GCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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

Last Updated: Mar 5, 2024

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