GUCY2D p.Phe565Ser

NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) is a missense variant predicted to replace phenylalanine with serine at position p.565. This variant is present in gnomAD v4.1.0 at a total allele frequency of 6.197e-7, with 1 allele / 1613704 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in a homozygous proband with early-onset severe retinal dystrophy in cis with the NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878ArgfsTer17) variant, which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (VCEP member-provided data, BP2). This variant has also been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 8944027), and in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant confirmed in trans with the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant (1 pt, PMID: 16505055), which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). Please note that one of these patients has been genotyped in a way that did not rule out the presence or absence of another GUCY2D variant in cis (PMID: 16505055). This proband exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset at 3 months (1 pt), night blindness (0.5 pts), nystagmus (1 pt), and visual acuity limited to light perception (1 pt), which together are specific for GUCYD2-related recessive retinopathy (total 4 pts, PMID: 16505055, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 3 similarly affected relatives in two different families, with the variant present in the homozygous state (PMID: 8944027, PP1_Strong). The computational predictor REVEL gives a score of 0.494, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 protein function. The variant exhibited inability to be stimulated by GCAP1 (PMID: 9888789), reduced RD3 binding by co-immunoprecipitation (PMID: 25477517), and failure to localize to the plasma membrane along with RD3 and GCAP1 when exogenously expressed (PMID: 25477517), indicating that it triggers a severe defect in protein function (PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1_Strong, PP4, and BP2. (VCEP specifications version 1.0.0; date of approval 01/22/2025).