NM_000161.3(GCH1):c.241T>C (p.Ser81Pro) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 25, 2021
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:: RCV001960944.6

Allele description [Variation Report for NM_000161.3(GCH1):c.241T>C (p.Ser81Pro)]

NM_000161.3(GCH1):c.241T>C (p.Ser81Pro)

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.241T>C (p.Ser81Pro)

HGVS:

NC_000014.9:g.54902423A>G
NG_008647.1:g.5402T>C
NM_000161.3:c.241T>CMANE SELECT
NM_001024024.2:c.241T>C
NM_001024070.2:c.241T>C
NM_001024071.2:c.241T>C
NP_000152.1:p.Ser81Pro
NP_001019195.1:p.Ser81Pro
NP_001019241.1:p.Ser81Pro
NP_001019242.1:p.Ser81Pro
NC_000014.8:g.55369141A>G

Protein change:

S81P

Links:

dbSNP: rs2140127208

NCBI 1000 Genomes Browser:

rs2140127208

Molecular consequence:

NM_000161.3:c.241T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024024.2:c.241T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024070.2:c.241T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024071.2:c.241T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dystonia 5 (DRD)
Synonyms:: Dystonia, progressive, with diurnal variation; Dystonia-Parkinsonism with diurnal fluctuation; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia; 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
SCV002239292	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 25, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20082337, 29290055, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002239292

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 25, 2021)

germline

clinical testing

PubMed (3)
[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

High frequency of multiexonic deletion of the GCH1 gene in a Taiwanese cohort of dopa-response dystonia.

Wu-Chou YH, Yeh TH, Wang CY, Lin JJ, Huang CC, Chang HC, Lai SC, Chen RS, Weng YH, Huang CL, Lu CS.

Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):903-8. doi: 10.1002/ajmg.b.31058.

PubMed [citation]

PMID:: 20082337

Variability of presynaptic nigrostriatal dopaminergic function and clinical heterogeneity in a dopa-responsive dystonia family with GCH-1 gene mutation.

Lin JJ, Lu CS, Tsai CH.

J Neurol. 2018 Mar;265(3):478-485. doi: 10.1007/s00415-017-8723-5. Epub 2017 Dec 30.

PubMed [citation]

PMID:: 29290055

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002239292.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with dystonia (PMID: 20082337, 29290055, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 81 of the GCH1 protein (p.Ser81Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline.

#	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: Sep 29, 2024

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