Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005053988 | SCV005687715 | likely pathogenic | GUCY2D-related recessive retinopathy | 2025-01-30 | reviewed by expert panel | curation | NM_000180.4(GUCY2D):c.743C>G (p.Ser248Trp) is a missense variant predicted to replace serine with tryptophan at position p.248 in the RetGC-1 protein. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000001240, with 2 alleles / 1,612,844 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 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.3224+1G>C variant suspected in trans (0.5 points, PMID: 23035049), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (0.5 total points, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), decreased central visual acuity (1 pt) with onset in the first year of life (1 pt), nystagmus (1 pt), decreased peripheral vision (1 pt), retinal vessel attenuation with granularity of peripheral fundus (0.5 pts), outer nuclear layer thickness on OCT within normal limits (1 pt), poor pupillary light response (0.5 pts), and undetectable electroretinogram responses from rods (0.5 pts). and cones (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 23035049, PP4). The computational predictor REVEL gives a score of 0.878, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). Gucy2e-knockout mouse retinas injected with an adeno-associated virus-packaged GUCY2D construct encoding the p.Ser248Trp variant showed mRNA levels similar to the wild-type control but dramatically reduced protein levels and essentially no cGMP production, indicating that it triggers a severe defect in protein function (PMID: 27881908, PS3_Supporting). Another missense variant in the same codon (NM_000180.4(GUCY2D):c.743C>T (p.Ser248Leu)) has been reported in association with GUCY2D-related recessive retinopathy (PMID: 26957854). However, the variant has not yet been classified by the LCA/eoRD VCEP, so the PM5 code is not met. 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, PP3_Moderate, PM3_Supporting, PP4, and PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). |
| Labcorp Genetics |
RCV001982693 | SCV002226953 | uncertain significance | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2021-07-14 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with tryptophan at codon 248 of the GUCY2D protein (p.Ser248Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is present in population databases (rs138922415, ExAC 0.002%). This missense change has been observed in individual(s) with autosomal recessive inherited retinal dystrophy (PMID: 23035049). 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 protein function (PMID: 23035049, 27881908). 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. |