Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000634833 | SCV000756177 | pathogenic | Dystonia 5; GTP cyclohydrolase I deficiency | 2023-12-13 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 108 of the GCH1 protein (p.Gly108Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dystonia (PMID: 9667588, 15753436; Invitae). ClinVar contains an entry for this variant (Variation ID: 9282). 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 expected to disrupt GCH1 protein function with a positive predictive value of 80%. This variant disrupts the p.Gly108 amino acid residue in GCH1. Other variant(s) that disrupt this residue have been observed in individuals with GCH1-related conditions (PMID: 16917893, 17898029), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV001659690 | SCV001880603 | pathogenic | not provided | 2021-05-07 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. The GCH1 gene is reported to exhibit gender-related incomplete penetrance of disease. Consistent with this variability, this variant has been reported in individuals with clinical presentations ranging from severe DRD, to adult-onset parkinsonism, to asymptomatic. Computational tools predict that this variant is damaging. |
| Gene |
RCV001659690 | SCV005325895 | uncertain significance | not provided | 2023-12-19 | criteria provided, single submitter | clinical testing | Identified with a second variant in this gene in a patient with motor delay, dysarthria, and dystonia (PMID: 9667588); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18044725, 19332422, 10984668, 9667588) |
| Mayo Clinic Laboratories, |
RCV001659690 | SCV005414217 | pathogenic | not provided | 2023-08-02 | criteria provided, single submitter | clinical testing | PP1, PP3, PP4, PM2_moderate, PM5, PS4 |
| OMIM | RCV002508113 | SCV000030085 | pathogenic | Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive | 1998-07-01 | no assertion criteria provided | literature only |