ClinVar Genomic variation as it relates to human health

Identified as a single heterozygous variant in patients with childhood or adult-onset dopa-responsive dystonia or adult-onset parkinsonism referred for genetic testing at GeneDx and in published literature, and also incidentally detected in an asymptomatic family member with low urinary neopterin levels (PMID: 23430498, 15303002, 24993959, 25497597, 12391354, 37165102, 38214203); Reported as a heterozygous variant in unrelated patients with dystonia whose asymptomatic relatives also harbored the variant (PMID: 36233161, 34890878); Observed with second GCH1 variant on the opposite allele (in trans) in a patient with gait abnormalities, wrist rigidity, dystonic posturing in the arm, curling and cramping of toes, and bradykinesia, as well as postload elevation in phenylalanine after phenylalanine loading (PMID: 35083481); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17044972, 33152132, 34497580, 20981092, 12391354, 15303002, 8852666, 25497597, 24993959, 10984668, 19332422, 18044725, 9667588, 29471552, 30894892, 30314816, 27313105, 31019283, 34426522, 35893043, 36833190, 35747429, 36628429, 34674384, 23942198, 37895316, 38214203, 37165102, 34890878, 23430498, 35083481, 36233161)

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families presenting with dopa-responsive dystonia (DRD). The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals ranging in presentation from severe DRD, to adult-onset parkinsonism, to asymptomatic.

The c.671A>G;p.(Lys224Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 12391354; 9667588; 8852666) - PS4. The p.(Lys224Arg) was detected in trans with a Pathogenic variant (PM3: PMID: 9667588) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 12391354; 8852666) - PP1.andallele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

The following ACMG criteria were applied in classifying this variant: PS4, PM2, PP1, PP2, PP5.

Variant summary: GCH1 c.671A>G (p.Lys224Arg) results in a conservative amino acid change located in the GTP cyclohydrolase I domain (IPR020602) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 248968 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GCH1 causing GTP Cyclohydrolase I Deficiency (0.00039 vs 0.0011), allowing no conclusion about variant significance. In a cross-sectional review, c.671A>G has been reported in the literature as a compound heterozygous genotype in individuals with autosomal recessive DOPA responsive dystonia (DRD) and in individuals with autosomal dominant features of athetoid cerebral palsy, GTP-CH deficiency, DRD, Parkinson disease (PD) (example, PMID: 19332422, 8852666, 9667588, 12391354, 18044725, 23942198, 17044972, 30314816). However, due to the presence in control cohorts, the possibility of reduced penetrance cannot be excluded. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 224 of the GCH1 protein (p.Lys224Arg). This variant is present in population databases (rs41298442, gnomAD 0.08%). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive dopa-responsive dystonia (PMID: 9667588, 12391354, 15303002, 17044972, 18044725, 19332422, 25497597, 30314816, 35083481). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This missense change has also been observed in the heterozygous state in unaffected individuals, consistent with reduced penetrance (PMID: 19332422, 23430498). ClinVar contains an entry for this variant (Variation ID: 9283). 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 80%. For these reasons, this variant has been classified as Pathogenic.

The c.671A>G (p.K224R) alteration is located in exon 6 (coding exon 6) of the GCH1 gene. This alteration results from a A to G substitution at nucleotide position 671, causing the lysine (K) at amino acid position 224 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.