Submissions for variant NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp)

gnomAD frequency: 0.00001  dbSNP: rs940175403

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV005053999	SCV005687763	pathogenic	GUCY2D-related recessive retinopathy	2025-01-30	reviewed by expert panel	curation	The NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp) variant is predicted to replace the arginine at position p.588 with tryptophan. The variant protein exhibited <1.5% of wild-type activity when stimulated with GCAP1, GCAP2, or GCAP3, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function. In addition, the variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting, PMID: 36274938). The computational predictor REVEL gives a score of 0.592, 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 splicing impact predictor SpliceAI gives a score of 0.2 for an acceptor site gain, which meets the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing, however, this variant has been curated based on protein function rather than spliceogenicity, so the PP3 code has not been considered. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000008678, with 14 alleles / 1,613,262 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 at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 29068479, 37327959). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2516del (p.Thr839ArgfsTer27) or the NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys) variant suspected but not confirmed in trans (PMID: 36274938, VCEP member-provided data), which have been previously classified as either pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state, and through a second proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID:37327959, VCEP member-provided data, PP1_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of early onset retinitis pigmentosa (0.5 pts) with onset in infancy (1 pt), genotyping by an LCA gene panel with no additional likely pathogenic findings (2 pts), electroretinogram showing altered responses from both cones and rods (1.5 pts), dyschromatopsia (1 pt), visual field loss (1 pt), attenuated blood vessels with peripheral pigment (0.5 pts), and night blindness (0.5 pts), which together are specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 37327959, PP4_moderate). 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, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003064395	SCV003443766	likely pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-04-18	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 588 of the GUCY2D protein (p.Arg588Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive Leber congenital amaurosis (PMID: 17964524, 26253563, 29068479, 32141364). ClinVar contains an entry for this variant (Variation ID: 2137915). 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: 36274938). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992701	SCV004809499	uncertain significance	Leber congenital amaurosis 1	2024-04-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817199	SCV005070145	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700917	SCV005205206	pathogenic	Leber congenital amaurosis	2024-06-14	criteria provided, single submitter	clinical testing	Variant summary: GUCY2D c.1762C>T (p.Arg588Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249900 control chromosomes (gnomAD). c.1762C>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis or Retinitis Pigmentosa (e.g. Stone_2007, Perez_Carro_2016, Srikrupa_2018, Jacobson_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in virtually no enzymatic activity in vitro (Jacobson_2022). The following publications have been ascertained in the context of this evaluation (PMID: 17964524, 26806561, 29068479, 36274938). ClinVar contains an entry for this variant (Variation ID: 2137915). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005019589	SCV005652770	likely pathogenic	Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i	2024-06-14	criteria provided, single submitter	clinical testing