Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005053960 | SCV005687742 | pathogenic | GUCY2D-related recessive retinopathy | 2025-01-30 | reviewed by expert panel | curation | NM_000180.4(GUCY2D):c.1245del (p.Phe415Leufs*73) is a loss of function variant in which the deletion of a T at c.1245 in exon 4 of 20 causes a frameshift and early termination 73 codons after p.Phe415. This premature stop codon 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 absent from gnomAD v. 4.1.0 (PM2_Supporting). The variant has been reported to segregate with LCA through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 32865313). The patient's phenotype or family history is highly specific for the gene, with at least one proband harboring this variant exhibiting a phenotype including a diagnosis of LCA / eoRD (0.5pts), previous genetic testing that did not provide an alternative explanation for visual impairment (2 pts), symptomatic onset between birth and 5 years (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), and decreased central vision (1 pt) which together are specific for GUCY2D-related recessive retinopathy (6.5 total points, PMID: 32865313, 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, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). |
| Mendelics | RCV000989736 | SCV001140280 | pathogenic | Cone-rod dystrophy 6 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001858713 | SCV002235919 | pathogenic | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2022-08-24 | 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: 803313). This premature translational stop signal has been observed in individual(s) with GUCY2D-related conditions (PMID: 32865313). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe415Leufs*73) 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). |