VCV000161247.44 - ClinVar

NM_000161.3(GCH1):c.206C>T (p.Pro69Leu)

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.

(9)

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
Uncertain significance(3); Benign(1); Likely benign(3)

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.206C>T (p.Pro69Leu)

Variation ID: 161247 Accession: VCV000161247.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q22.2 14: 54902458 (GRCh38) [ NCBI UCSC ] 14: 55369176 (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	Dec 7, 2014	Oct 20, 2024	Nov 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000161.3:c.206C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000152.1:p.Pro69Leu	missense
NM_001024024.2:c.206C>T	NP_001019195.1:p.Pro69Leu	missense
NM_001024070.2:c.206C>T	NP_001019241.1:p.Pro69Leu	missense
NM_001024071.2:c.206C>T	NP_001019242.1:p.Pro69Leu	missense
NC_000014.9:g.54902458G>A
NC_000014.8:g.55369176G>A
NG_008647.1:g.5367C>T

... more HGVS ... less HGVS

Protein change

P69L

Other names

Canonical SPDI

NC_000014.9:54902457:G:A

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.

0.00040 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD) 0.00035

Exome Aggregation Consortium (ExAC) 0.00036

1000 Genomes Project 0.00040

Trans-Omics for Precision Medicine (TOPMed) 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00044

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

Links

ClinGen: CA211433 dbSNP: rs56127440 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	452	552

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	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 12, 2019	RCV000362082.8
Dystonia 5 GTP cyclohydrolase I deficiency	Uncertain significance (1)	criteria provided, single submitter	Nov 1, 2022	RCV000687434.8
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Dec 1, 2021	RCV000585377.28
GCH1-related disorder	Likely benign (1)	no assertion criteria provided	Jan 22, 2024	RCV003917463.2
Hyperphenylalaninemia due to tetrahydrobiopterin deficiency	Likely benign (1)	no assertion criteria provided	Jun 1, 2014	RCV000148505.4
GTP cyclohydrolase I deficiency	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000265088.7

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.
Likely benign (Dec 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000692790.30 First in ClinVar: Mar 03, 2018 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Uncertain significance (Dec 14, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143995.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (8) PubMed: 24993959‚ 26230973‚ 19491146‚ 25497597‚ 30314816‚ 27185167‚ 25125585‚ 15389992
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	GTP cyclohydrolase I deficiency with hyperphenylalaninemia Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139462.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	GTP cyclohydrolase I deficiency with hyperphenylalaninemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000387121.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 15389992‚ 19491146 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dystonia 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000387120.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 19491146‚ 15389992 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Sep 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dystonia 5 Affected status: yes Allele origin: paternal	Centogene AG - the Rare Disease Company Accession: SCV002059427.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Uncertain significance (Nov 01, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	GTP cyclohydrolase I deficiency Dystonia 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000814999.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023	Publications: PubMed (9) PubMed: 28492532‚ 15389992‚ 19491146‚ 25125585‚ 25398234‚ 26230973‚ 27185167‚ 27217339‚ 30314816 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the GCH1 protein (p.Pro69Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the GCH1 protein (p.Pro69Leu). This variant is present in population databases (rs56127440, gnomAD 0.2%). This missense change has been observed in individual(s) with dystonia, parkinsonism, and hereditary spastic paraplegia (PMID: 15389992, 19491146, 25125585, 25398234, 26230973, 27185167, 27217339, 30314816). ClinVar contains an entry for this variant (Variation ID: 161247). 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. (less)
Likely benign (Jan 22, 2024)	no assertion criteria provided Method: clinical testing	GCH1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004729179.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (Jun 01, 2014)	no assertion criteria provided Method: research	Tetrahydrobiopterin deficiency (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190216.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 69 of the GCH1 protein (p.Pro69Leu). This variant is present in population databases (rs56127440, gnomAD 0.2%). This missense change has been observed in individual(s) with dystonia, parkinsonism, and hereditary spastic paraplegia (PMID: 15389992, 19491146, 25125585, 25398234, 26230973, 27185167, 27217339, 30314816). ClinVar contains an entry for this variant (Variation ID: 161247). 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.

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
Common and rare GCH1 variants are associated with Parkinson's disease.	Rudakou U	Neurobiology of aging	2019	PMID: 30314816
Genetic and phenotypic characterization of complex hereditary spastic paraplegia.	Kara E	Brain : a journal of neurology	2016	PMID: 27217339
Low frequency of GCH1 and TH mutations in Parkinson's disease.	Rengmark A	Parkinsonism & related disorders	2016	PMID: 27185167
Premotor-motor excitability is altered in dopa-responsive dystonia.	Weissbach A	Movement disorders : official journal of the Movement Disorder Society	2015	PMID: 26230973
Parkinsonism in GTP cyclohydrolase 1 mutation carriers.	Guella I	Brain : a journal of neurology	2015	PMID: 25497597
Reply: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.	Mencacci NE	Brain : a journal of neurology	2015	PMID: 25398234
Hereditary dystonia and parkinsonism: two sides of the same coin?	Weissbach A	Brain : a journal of neurology	2014	PMID: 25125585
Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.	Mencacci NE	Brain : a journal of neurology	2014	PMID: 24993959
Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia.	Clot F	Brain : a journal of neurology	2009	PMID: 19491146
Amantadine for levodopa-induced choreic dyskinesia in compound heterozygotes for GCH1 mutations.	Furukawa Y	Movement disorders : official journal of the Movement Disorder Society	2004	PMID: 15389992

Text-mined citations for rs56127440 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000161.3(GCH1):c.206C>T (p.Pro69Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs56127440 ...