ClinVar Miner

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

gnomAD frequency: 0.00019  dbSNP: rs61750168
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000084856 SCV000322380 pathogenic not provided 2025-01-04 criteria provided, single submitter clinical testing Observed with an additional variant in the GUCY2D gene in patients with Leber congenital amaurosis in published literature, although it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Yzer et al., 2006; Coppieters et al., 2012; Astuti et al., 2016; Thompson et al., 2017); Published functional studies demonstrate a damaging effect with reduction in GUCY2D enzyme activation in the presence of GCAP1, diminished binding to GCAP1, and altered GCAP1 co-localization (Peshenko et al., 2010); 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: 26253563, 18632300, 21602930, 20683928, 23035049, 25477517, 26626312, 31429209, 10766140, 16505055, 29178642, 29559409, 16272259, 34426522, 31589614, 31964843, 37734845, 20050595, 22261762, 31816670, 32865313, 34008892, 35314386, 36369640, 37327959, 37510321, 34048777, 35836572, 36460718, 33109612)
Labcorp Genetics (formerly Invitae), Labcorp RCV000543628 SCV000649515 pathogenic Cone-rod dystrophy 6; Leber congenital amaurosis 1 2024-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 768 of the GUCY2D protein (p.Arg768Trp). This variant is present in population databases (rs61750168, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 16505055, 17724218, 23035049, 26253563, 26626312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98563). 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 GUCY2D protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GUCY2D function (PMID: 20050595, 25477517). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002477250 SCV000893483 pathogenic Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i 2024-05-03 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075745 SCV001241375 pathogenic Retinal dystrophy 2019-05-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000084856 SCV001248902 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000084856 SCV001473743 pathogenic not 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000850093 SCV001976832 pathogenic Leber congenital amaurosis 1 2021-10-01 criteria provided, single submitter clinical testing PS3, PM2, PP1, PP3, PP4, PP5
Institute of Human Genetics, University of Leipzig Medical Center RCV000850093 SCV003921083 pathogenic Leber congenital amaurosis 1 2023-03-02 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PM3_STR, PS3_MOD, PM5, PM2_SUP, PP3
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV001075745 SCV005072449 pathogenic Retinal dystrophy 2020-01-01 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000850093 SCV005399407 pathogenic Leber congenital amaurosis 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with Leber congenital amaurosis 1 (LCA, MIM#204000) and gain of function variants are associated with Cone-rod dystrophy 6 (MIM#601777). Gain of function variants tend to cluster in the linker domain specifically around p.838 (OMIM, PMIDs: 29061346, 11709018, 11115851). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygotes with autosomal dominant disease tend to be less severely affected (OMIM, PMID: 29061346). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (40 heterozygotes, 0 homozygotes). This variant has been described as a founder mutation in northwest European populations (PMID: 16505055). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The missense variant, p.(Arg768Gln) has been observed in two individuals with LCA (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in greater than ten individuals with LCA in both compound heterozygous and homozygous states (ClinVar, LOVD, PMID: 16505055). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Retina International RCV000084856 SCV000116992 not provided not provided no assertion provided not provided
Department of Clinical Genetics, Copenhagen University Hospital, 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
PreventionGenetics, part of Exact Sciences RCV004748575 SCV005361417 pathogenic GUCY2D-related disorder 2024-09-18 no assertion criteria provided clinical testing The GUCY2D c.2302C>T variant is predicted to result in the amino acid substitution p.Arg768Trp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Leber congenital amaurosis type 1 (LCA1) (for example, see Jacobson et al. 2013. PubMed ID: 23035049; Thompson et al. 2017. PubMed ID: 29178642; Stunkel et al. 2018. PubMed ID: 29559409). This variant has also been shown to co-segregate with disease in a Polish family (Skorczyk-Werner et al. 2022. PubMed ID: 36369640). In vitro functional studies have demonstrated that the p.Arg768Trp variant disrupts protein-protein interactions required for protein activation and proper intracellular localization, leading to a complete loss of function (Peshenko et al. 2010. PubMed ID: 20050595; Jacobson et al. 2013. PubMed ID: 23035049; Zulliger et al. 2015. PubMed ID: 25477517; Peshenko et al. 2020. PubMed ID: 33109612). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, a different missense variant at the same amino acid position (p.Arg768Gln) has also been reported as disease-causing in LCA1 patients (Wiszniewski et al. 2011. PubMed ID: 21153841; Wang et al. 2015. PubMed ID: 26047050; Sharon et al. 2019. PubMed ID: 31456290). Taken together, the p.Arg768Trp variant is interpreted as pathogenic.

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