Submissions for variant NM_000161.3(GCH1):c.671A>G (p.Lys224Arg)

gnomAD frequency: 0.00039  dbSNP: rs41298442

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517539	SCV000613388	likely pathogenic	not provided	2021-03-15	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000525589	SCV000631821	pathogenic	Dystonia 5; GTP cyclohydrolase I deficiency	2024-01-30	criteria provided, single submitter	clinical testing	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000009865	SCV000883144	pathogenic	Dystonia 5	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000989227	SCV001139460	likely pathogenic	GTP cyclohydrolase I deficiency	2021-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000517539	SCV001795884	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Reported previously as a maternally inherited variant, in trans with a paternally inherited variant (on a different allele), in a patient with gait abnormalities, significant diurnal variation of symptoms, wrist rigidity, dystonic posturing in the arm, curling and cramping of toes, and bradykinesia, as well as postload elevation in phenylalanine after phenylalanine loading (Berger et al., 2022); Reported previously as a heterozygous variant in a patient with GP T2 hypointensity, dystonia, dysarthria, and upper limb tremor; however, two asymptomatic children also harbored the variant (Martnez-Rubio et al., 2022); 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, 23430498, 19332422, 18044725, 9667588, 29471552, 30894892, 30314816, 27313105, 31019283, 34426522, 35893043, 36833190, 34890878, 35747429, 36628429, 34674384, 36233161, 35083481)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009865	SCV002102435	uncertain significance	Dystonia 5	2022-02-09	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_SUP, PM1_SUP
DASA	RCV002255090	SCV002526412	likely pathogenic	Dopa-responsive dystonia	2022-06-10	criteria provided, single submitter	clinical testing	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
Ambry Genetics	RCV002512951	SCV003713991	uncertain significance	Inborn genetic diseases	2021-11-18	criteria provided, single submitter	clinical testing	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.
Genetic Medical Diagnostic Laboratory CellGenetics, GMDL CellGenetics	RCV000009865	SCV003804499	likely pathogenic	Dystonia 5		criteria provided, single submitter	clinical testing	The following ACMG criteria were applied in classifying this variant: PS4, PM2, PP1, PP2, PP5.
Revvity Omics, Revvity	RCV000517539	SCV003814498	uncertain significance	not provided	2022-04-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000989227	SCV003922546	pathogenic	GTP cyclohydrolase I deficiency	2023-03-11	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000517539	SCV004033301	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	GCH1: PM1, PS4:Moderate, PP1, PP2
OMIM	RCV000009865	SCV000030086	pathogenic	Dystonia 5	2002-10-22	no assertion criteria provided	literature only
OMIM	RCV002508114	SCV000030087	pathogenic	Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive	2002-10-22	no assertion criteria provided	literature only