Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005053905 | SCV005687714 | likely pathogenic | GUCY2D-related recessive retinopathy | 2025-01-30 | reviewed by expert panel | curation | NM_000180.4(GUCY2D):c.937C>T (p.Arg313Cys) is a missense variant predicted to replace arginine with cysteine at position p.313. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000009334, with 15 alleles / 1,607,084 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 probands with early-onset severe retinal dystrophy who also harbored either the NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter) variant (suspected but not confirmed in trans, PMID:10951519) or the NM_000180.4(GUCY2D):c.3078_3083dup (p.Ile1027_Leu1028dup) variant (confirmed in trans, PMID: 34048777), each which have been previously classified as either pathogenic or likely pathogenic by the LCA/eoRD VCEP (1.5 total pts, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (VCEP member-provided data, PP1). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts) with onset at age 0.3 years (1 pt), genotyping by exome sequencing with no alternative cause of retinal disease identified (4 pts), poor vision with no light perception (1 pt), roving nystagmus (1 pt), attenuated vessels (0.5 pts), and extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (9.5 total points, PMID: 34048777, PP4_Moderate). 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: PM2_Supporting, PM3, PP1, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025). |
| Labcorp Genetics |
RCV001306870 | SCV001496255 | uncertain significance | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2022-02-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 313 of the GUCY2D protein (p.Arg313Cys). This variant is present in population databases (rs61749674, gnomAD 0.007%). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 10951519, 34048777; Invitae). ClinVar contains an entry for this variant (Variation ID: 98611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GUCY2D function (PMID: 11328726). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Gene |
RCV000084907 | SCV001986110 | uncertain significance | not provided | 2020-04-29 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed with a pathogenic variant in a patient with Leber congenital amaurosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Perrault et al., 2000); This variant is associated with the following publications: (PMID: 10951519) |
| Retina International | RCV000084907 | SCV000117043 | not provided | not provided | no assertion provided | not provided | ||
| Laboratory of Genetics in Ophthalmology, |
RCV001250827 | SCV001426314 | likely pathogenic | Leber congenital amaurosis 1 | no assertion criteria provided | research |