Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005053903 | SCV005687757 | pathogenic | GUCY2D-related recessive retinopathy | 2025-01-31 | reviewed by expert panel | curation | NM_000180.4(GUCY2D):c.91dup (p.Arg31ProfsTer?) is a frameshift variant that introduces a premature stop codon into exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000009890, with 15 alleles / 1516748 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat electroretinogram responses from both rods (0.5 pts) and cones (1 pt), high hypermetropia, being drawn to bright light, sluggish pupillary responses (0.5 pts), eye poking, and normal appearing fundus, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 29178642, PP4). 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: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). |
| Labcorp Genetics |
RCV002513910 | SCV003513828 | pathogenic | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2023-04-09 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 98609). This premature translational stop signal has been observed in individuals with autosomal recessive leber congenital amaurosis (PMID: 15024725, 29178642). This variant is present in population databases (rs61749663, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg31Profs*288) in the GUCY2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GUCY2D are known to be pathogenic (PMID: 10951519, 11328726). |
| Retina International | RCV000084905 | SCV000117041 | not provided | not provided | no assertion provided | not provided | ||
| Laboratory of Genetics in Ophthalmology, |
RCV001250872 | SCV001426364 | pathogenic | Leber congenital amaurosis 1 | no assertion criteria provided | research |