Submissions for variant NM_000161.3(GCH1):c.10G>A (p.Gly4Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003131003	SCV003814501	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778702	SCV004585271	uncertain significance	Dystonia 5; GTP cyclohydrolase I deficiency	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4 of the GCH1 protein (p.Gly4Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2432081). 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 with a negative predictive value of 95%. 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.
Ambry Genetics	RCV004245994	SCV004873345	uncertain significance	Inborn genetic diseases	2023-12-09	criteria provided, single submitter	clinical testing	The c.10G>A (p.G4S) alteration is located in exon 1 (coding exon 1) of the GCH1 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the glycine (G) at amino acid position 4 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.