Submissions for variant NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) (rs61750168)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000084856	SCV000322380	pathogenic	not provided	2016-04-04	criteria provided, single submitter	clinical testing	The R768W variant in the GUCY2D gene has been reported previously in the heterozygous, homozygous, and compound heterozygous state in multiple unrelated individuals with Leber congenital amaurosis, and may represent a European founder mutation (Lotery et al., 2000; Booij et al., 2005; Astuti et al., 2015; Peshenko et al., 2010; Yzer et al., 2006; Coppieters et al., 2012). Functional studies of the R768W variant in HEK293 cells resulted in a dramatic reduction in GUCY2D enzyme activation in the presence of GCAP1, diminished binding to GCAP1, and altered GCAP1 co-localization (Peshenko et al., 2010). The R768W variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R768W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret R768W as a pathogenic variant.
Invitae	RCV000543628	SCV000649515	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 768 of the GUCY2D protein (p.Arg768Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs61750168, ExAC 0.03%). This variant has been reported in the homozygous or compound heterozygous state in many individuals affected with Leber congenital amaurosis (PMID: 23035049, 17724218, 26626312, 26253563, 16505055). ClinVar contains an entry for this variant (Variation ID: 98563). Experimental studies have shown that this missense change severely impairs binding to RD3 and is enzymatically inactive, even at saturating concentrations of GCAP1 (PMID: 20050595, 25477517). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000763023	SCV000893483	pathogenic	Choroidal dystrophy, central areolar 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075745	SCV001241375	pathogenic	Retinal dystrophy	2019-05-22	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000084856	SCV001248902	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001287097	SCV001473743	pathogenic	none provided	2020-01-07	criteria provided, single submitter	clinical testing	The GUCY2D c.2302C>T; p.Arg768Trp variant (rs61750168) is reported in the medical literature in several individuals and families with retinal disease in both the homozygous and compound heterozygous state (Peshenko 2010, Stunkel 2018, Thompson 2017, Yzer 2006, Zulliger 2015) The variant is reported as pathogenic or likely pathogenic in the ClinVar database (Variation ID: 98563) and is listed in the general population with an allele frequency of 0.014% (40/282,714 alleles) in the Genome Aggregation Database. The arginine at codon 768 is highly conserved, located in the catalytic domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In support of this prediction, this variant is defective in functional studies (Jacobsen 2013, Zulliger 2015). Considering available information, this variant is classified as pathogenic. References: Jacobson SG et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013 Jan 1;22(1):168-83. Peshenko IV et al. Activation of retinal guanylyl cyclase RetGC1 by GCAP1: stoichiometry of binding and effect of new LCA-related mutations. Biochemistry. 2010 Feb 2;49(4):709-17. Stunkel ML et al. Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D. Am J Ophthalmol. 2018 Jun;190:58-68. Thompson JA et al. The genetic profile of Leber congenital amaurosis in an Australian cohort. Mol Genet Genomic Med. 2017 Nov;5(6):652-667. Yzer S et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1167-76. Zulliger R et al. Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem. 2015 Feb 6;290(6):3488-99.
Retina International	RCV000084856	SCV000116992	not provided	not provided		no assertion provided	not provided
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000787613	SCV000926597	likely pathogenic	Leber congenital amaurosis	2018-04-01	no assertion criteria provided	research
OMIM	RCV000850093	SCV000992257	pathogenic	Leber congenital amaurosis 1	2019-09-03	no assertion criteria provided	literature only
OMIM	RCV000850094	SCV000992258	pathogenic	Night blindness, congenital stationary, type1i	2019-09-03	no assertion criteria provided	literature only
Laboratory of Genetics in Ophthalmology,Institut Imagine	RCV000850093	SCV001426328	pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	research