ClinVar Genomic variation as it relates to human health

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 204 of the GCH1 protein (p.Val204Ile). This variant is present in population databases (rs200891969, gnomAD 0.1%). This missense change has been observed in individual(s) with dopa-responsive dystonia and/or guanine triphosphate cyclohydrolase type I deficiency without hyperphenylalaninemia (PMID: 12874420, 19332422, 20818608, 24993959, 27666935, 30911941). ClinVar contains an entry for this variant (Variation ID: 161248). 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.

Identified in the heterozygous state in individuals with dopa-responsive dystonia in whom no second variant was identified (PMID: 26230973, 27666935); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30911941, 25637381, 25525159, 20818608, 27666935, 19332422, 12874420, 30314816, 31213404, 24993959, 29484265, 32740907, 31996268, 35287262, 34670123, 34999542, 34674384, 26230973)

A Heterozygous Missense variant c.610G>A in Exon 5 of the GCH1 gene that results in the amino acid substitution p.Val204Ile was identified. The observed variant has a maximum allele frequency of 0.00022/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as (Likely Pathogenic/Uncertain Significance) Conflicting Interpretations [Variation ID: 161248]. The observed variation has been previously reported in patients affected with Early-Onset Generalized Dystonia (Zech M, et.al., 2017). For these reasons, this variant has been classified as Likely Pathogenic.

Variant summary: GCH1 c.610G>A (p.Val204Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251266 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GCH1 causing GTP Cyclohydrolase I Deficiency (0.00022 vs 0.0011), allowing no conclusion about variant significance. c.610G>A has been reported in the literature as compound heterozygote DOPA naive dystonia with normal serum prolactin levels (example, Furukawa_2003), early infantile onset autosomal recessive GTP Cyclohydrolase I Deficiency without Hyperphenylalaninemia (example, Opaladen_2011), DOPA responsive dystonia in compound heterozygosity where the other variant explained the phenotype and asymptomatic heterozygous family members (example, Menacci_2014, Giri_2019), generalized dystonia non responsive to DOPA (example, Beom Ahn_2019, Zech_2017), and at unknown zygosity with Transposition of the great arterie and Parkinson's disease (Blue_2022, Muldmaa_2021). These report(s) do not provide unequivocal conclusions about association of the variant with GTP Cyclohydrolase I Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31213404, 34670123, 12874420, 30911941, 24993959, 32740907, 20818608, 27666935). ClinVar contains an entry for this variant (Variation ID: 161248). Based on the evidence outlined above, the variant was classified as uncertain significance.

Criteria applied: PM3_STR,PM1,PM2_SUP,PP3