Submissions for variant NM_000180.4(GUCY2D):c.2927G>T (p.Arg976Leu)

dbSNP: rs61750184

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	RCV005053897	SCV005687719	likely pathogenic	GUCY2D-related recessive retinopathy	2025-01-30	reviewed by expert panel	curation	NM_000180.4(GUCY2D):c.2927G>T (p.Arg976Leu) is a missense variant that replaces arginine with leucine at position p.976, which is located within the active site, a well-characterized functional domain that binds the GTP substrate and the Mg ion and is required for enzymatic activity (PM1, PMID: 9391039). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 total points, PMID: 10951519, PM3_Supporting). A second proband was not only homozygous for this variant but also for the NM_000180.4(GUCY2D):c.2766C>G (p.Tyr922Ter) variant, and so was not counted for the PM3 code (PMID: 24265693). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), severely reduced vision (1 pt) with onset from birth (1 pt), nystagmus (1 pt), unremarkable fundus, irregular pigmentation (0.5 pts), hypermetropia, electroretinogram responses below the detection limit from both rods (0.5 pts) and cones (1 pt), and macular atrophy, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 17525851, PP4). The computational predictor REVEL gives a score of 0.895, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). The variant exhibited 0% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, 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 (PMID: 11328726, PS3_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM1, PM2_Supporting, PM3_Supporting, PP4, PP3_Moderate, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714548	SCV000845248	uncertain significance	Cone-rod dystrophy 6	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714549	SCV000845249	uncertain significance	Leber congenital amaurosis 1	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714550	SCV000845250	uncertain significance	Choroidal dystrophy, central areolar, 1	2018-08-07	criteria provided, single submitter	clinical testing
Retina International	RCV000084876	SCV000117012	not provided	not provided		no assertion provided	not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV000714549	SCV001426341	likely pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	research