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

gnomAD frequency: 0.00035  dbSNP: rs56127440

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000362082	SCV000387120	likely benign	Dystonia 5	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000265088	SCV000387121	likely benign	GTP cyclohydrolase I deficiency	2017-04-27	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000585377	SCV000692790	likely benign	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000687434	SCV000814999	uncertain significance	Dystonia 5; GTP cyclohydrolase I deficiency	2022-11-01	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000265088	SCV001139462	benign	GTP cyclohydrolase I deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000585377	SCV001143995	uncertain significance	not provided	2018-12-14	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000362082	SCV002059427	uncertain significance	Dystonia 5	2019-09-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917463	SCV004729179	likely benign	GCH1-related condition	2024-01-22	criteria provided, single submitter	clinical testing	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).
CSER _CC_NCGL, University of Washington	RCV000148505	SCV000190216	likely benign	Hyperphenylalaninemia due to tetrahydrobiopterin deficiency	2014-06-01	no assertion criteria provided	research