Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002057 | SCV001159886 | pathogenic | not specified | 2018-09-01 | criteria provided, single submitter | clinical testing | The GUCY2D c.2513G>C; p.Arg838Pro variant is reported in the medical literature in individuals and families with autosomal dominant cone-rod dystrophy, cone dystrophy, and macular degeneration (Garcia-Hoyos 2011, Jiang 2015, Xu 2013). The variant is reported as occurring de novo in at least one affected individual and segregates with disease in other families (Garcia-Hoyos 2011, Jiang 2015, Xu 2013). Additionally, other variants at this codon (p.Ag838Cys, p.Arg838Gly, p.Arg838His) have also been reported in affected individuals (Jiang 2015, Kitiratschky 2008). The p.Arg838Pro variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In agreement with this prediction, arginine 838 has been shown to be critical for calcium binding and protein dimerization and other variants in this codon disrupt this critical function in vitro (Ramamurthy 2001). Considering available information, this variant is classified as pathogenic. Pathogenic GUCY2D variants are causative for autosomal dominant or recessive cone-rod dystrophy (MIM: 601777) or autosomal recessive Leber congenital amaurosis (MIM: 204000). Most pathogenic variants associated with GUCY2D autosomal dominant cone degeneration or cone-rod degeneration occur in amino acid residue p.Arg838 (Kitiratschky 2008). References: Garcia-Hoyos M et al. Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish families with autosomal dominant cone, cone-rod, and macular dystrophies. Mol Vis. 2011 Apr 29;17:1103-9. Jiang F et al. GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies. Doc Ophthalmol. 2015 Oct;131(2):105-14 . Kitiratschky VB et al. Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Invest Ophthalmol Vis Sci 2008 Nov;49(11):5015-5023. Ramamurthy V et al. Interactions within the coiled-coil domain of RetGC-1 guanylyl cyclase are optimized for regulation rather than for high affinity. J Biol Chem. 2001 Jul 13;276(28):26218-29. Xu F et a. Phenotypic characterization of a Chinese family with autosomal dominant cone-rod dystrophy related to GUCY2D. Doc Ophthalmol. 2013 Jun;126(3):233-40. |
| Blueprint Genetics | RCV001075542 | SCV001241168 | pathogenic | Retinal dystrophy | 2018-12-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001869428 | SCV002201927 | pathogenic | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2023-08-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 838 of the GUCY2D protein (p.Arg838Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cone-rod dystrophy (PMID: 26298565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 811743). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. This variant disrupts the p.Arg838 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618177, 15175914, 26298565). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |