VCV000009282.14 - ClinVar

NM_000161.3(GCH1):c.323G>A (p.Gly108Asp)

Germline

Classification

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.

(5)

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.

Conflicting classifications of pathogenicity
Pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000161.3(GCH1):c.323G>A (p.Gly108Asp)

Variation ID: 9282 Accession: VCV000009282.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q22.2 14: 54902341 (GRCh38) [ NCBI UCSC ] 14: 55369059 (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	Aug 22, 2016	Nov 24, 2024	Dec 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000161.3:c.323G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000152.1:p.Gly108Asp	missense
NM_001024024.2:c.323G>A	NP_001019195.1:p.Gly108Asp	missense
NM_001024070.2:c.323G>A	NP_001019241.1:p.Gly108Asp	missense
NM_001024071.2:c.323G>A	NP_001019242.1:p.Gly108Asp	missense
NC_000014.9:g.54902341C>T
NC_000014.8:g.55369059C>T
NG_008647.1:g.5484G>A
	P30793:p.Gly108Asp

... more HGVS ... less HGVS

Protein change

G108D

Other names

Canonical SPDI

NC_000014.9:54902340:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA120279 UniProtKB: P30793#VAR_016894 OMIM: 600225.0012 dbSNP: rs104894435 VarSome

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
Gene	OMIM	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.
GCH1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	453	553

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.
Dystonia 5 GTP cyclohydrolase I deficiency	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2023	RCV000634833.18
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Dec 19, 2023	RCV001659690.11
Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive	Pathogenic (1)	no assertion criteria provided	Jul 1, 1998	RCV002508113.8

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 (May 07, 2021)	criteria provided, single submitter (Athena Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001880603.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (6) PubMed: 12112113‚ 15753436‚ 9667588‚ 21412842‚ 1449240‚ 8298648 Comment: This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. The GCH1 gene is reported … (more) This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals with clinical presentations ranging from severe DRD, to adult-onset parkinsonism, to asymptomatic. Computational tools predict that this variant is damaging. (less)
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	GTP cyclohydrolase I deficiency Dystonia 5 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000756177.8 First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 9667588‚ 15753436‚ 16917893‚ 17898029 Comment: This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 108 of the GCH1 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 108 of the GCH1 protein (p.Gly108Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dystonia (PMID: 9667588, 15753436; Invitae). ClinVar contains an entry for this variant (Variation ID: 9282). 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 expected to disrupt GCH1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly108 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 16917893, 17898029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Dec 19, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005325895.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024	Comment: Identified with a second variant in this gene in a patient with motor delay, dysarthria, and dystonia (PMID: 9667588); Not observed at significant frequency in … (more) Identified with a second variant in this gene in a patient with motor delay, dysarthria, and dystonia (PMID: 9667588); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18044725, 19332422, 10984668, 9667588) (less)
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414217.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 12112113‚ 15753436‚ 16917893‚ 17898029‚ 19332422‚ 21412842‚ 9667588 Comment: PP1, PP3, PP4, PM2_moderate, PM5, PS4 Number of individuals with the variant: 1
Pathogenic (Jul 01, 1998)	no assertion criteria provided Method: literature only	DYSTONIA, DOPA-RESPONSIVE, WITH OR WITHOUT HYPERPHENYLALANINEMIA, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030085.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 9667588 Comment on evidence: In a 17-year-old male with dopa-responsive dystonia (see 233910) Furukawa et al. (1998) identified a novel G-A transition in exon 1 of the GCH1 gene, … (more) In a 17-year-old male with dopa-responsive dystonia (see 233910) Furukawa et al. (1998) identified a novel G-A transition in exon 1 of the GCH1 gene, resulting in a gly108-to-asp (G108D) substitution, which was inherited from his asymptomatic father, who was not examined. The patient was a compound heterozygote for an additional mutation in the GCH1 gene, an A-G transition in exon 6, resulting in a lys224-to-arg (K224R) substitution (600225.0013), which he had inherited from his asymptomatic mother. The boy could not walk until age 4, at which time language was normal except for mild dysarthria. Between the ages of 4 and 6 years, the patient's previously acquired motor and speech functions deteriorated, and he subsequently became wheelchair bound and mute. (less)

Comment:

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals with clinical presentations ranging from severe DRD, to adult-onset parkinsonism, to asymptomatic. Computational tools predict that this variant is damaging.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 108 of the GCH1 protein (p.Gly108Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dystonia (PMID: 9667588, 15753436; Invitae). ClinVar contains an entry for this variant (Variation ID: 9282). 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 expected to disrupt GCH1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly108 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 16917893, 17898029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Comment:

Identified with a second variant in this gene in a patient with motor delay, dysarthria, and dystonia (PMID: 9667588); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18044725, 19332422, 10984668, 9667588)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The association of Tourette syndrome and dopa-responsive dystonia.	Yaltho TC	Movement disorders : official journal of the Movement Disorder Society	2011	PMID: 21412842
Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients.	Trender-Gerhard I	Journal of neurology, neurosurgery, and psychiatry	2009	PMID: 19332422
Frequency of GCH1 deletions in Dopa-responsive dystonia.	Zirn B	Journal of neurology, neurosurgery, and psychiatry	2008	PMID: 17898029
Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase.	Thöny B	Human mutation	2006	PMID: 16917893
High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening.	Hagenah J	Neurology	2005	PMID: 15753436
Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia.	Furukawa Y	Annals of neurology	2002	PMID: 12112113
Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.	Furukawa Y	Annals of neurology	1998	PMID: 9667588
Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q.	Nygaard TG	Nature genetics	1993	PMID: 8298648
Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia.	Nygaard TG	Annals of neurology	1992	PMID: 1449240

Text-mined citations for rs104894435 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000161.3(GCH1):c.323G>A (p.Gly108Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894435 ...