NM_000161.3(GCH1):c.328C>G (p.Gln110Glu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 28, 2022
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:: RCV001063206.7

Allele description [Variation Report for NM_000161.3(GCH1):c.328C>G (p.Gln110Glu)]

NM_000161.3(GCH1):c.328C>G (p.Gln110Glu)

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.328C>G (p.Gln110Glu)

HGVS:

NC_000014.9:g.54902336G>C
NG_008647.1:g.5489C>G
NM_000161.3:c.328C>GMANE SELECT
NM_001024024.2:c.328C>G
NM_001024070.2:c.328C>G
NM_001024071.2:c.328C>G
NP_000152.1:p.Gln110Glu
NP_001019195.1:p.Gln110Glu
NP_001019241.1:p.Gln110Glu
NP_001019242.1:p.Gln110Glu
NC_000014.8:g.55369054G>C
NM_000161.2:c.328C>G

Protein change:

Q110E

Links:

dbSNP: rs748944982

NCBI 1000 Genomes Browser:

rs748944982

Molecular consequence:

NM_000161.3:c.328C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024024.2:c.328C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024070.2:c.328C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024071.2:c.328C>G - 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
SCV001228042	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 28, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24993959, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001228042

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 28, 2022)

germline

clinical testing

PubMed (2)
[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

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.

Mencacci NE, Isaias IU, Reich MM, Ganos C, Plagnol V, Polke JM, Bras J, Hersheson J, Stamelou M, Pittman AM, Noyce AJ, Mok KY, Opladen T, Kunstmann E, Hodecker S, Münchau A, Volkmann J, Samnick S, Sidle K, Nanji T, Sweeney MG, Houlden H, et al.

Brain. 2014 Sep;137(Pt 9):2480-92. doi: 10.1093/brain/awu179. Epub 2014 Jul 2.

PubMed [citation]

PMID:: 24993959
PMCID:: PMC4132650

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001228042.4

#	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 glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 110 of the GCH1 protein (p.Gln110Glu). This variant is present in population databases (rs748944982, gnomAD 0.02%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 24993959). ClinVar contains an entry for this variant (Variation ID: 444330). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GCH1 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

Last Updated: Oct 20, 2024

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