Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005053891 | SCV005687710 | uncertain significance | GUCY2D-related recessive retinopathy | 2025-01-30 | reviewed by expert panel | curation | The NM_000180.4(GUCY2D):c.1618C>T (p.Arg540Cys) variant is predicted to replace the arginine at position p.540 with cysteine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.00005391, with 87 alleles / 1,613,652 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. This variant was reported in individual with LCA but no second variant was identified. It was also seen heterozygously in a patient with a macular dystrophy likely caused by ABCA4 variants (PM3_not met; PMIDs:10951519, 29555955). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). |
| Labcorp Genetics |
RCV001854485 | SCV002316120 | uncertain significance | Cone-rod dystrophy 6; Leber congenital amaurosis 1 | 2022-08-16 | 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 540 of the GUCY2D protein (p.Arg540Cys). This variant is present in population databases (rs61749754, gnomAD 0.008%). This missense change has been observed in individual(s) with GUCY2D-related conditions (PMID: 10951519, 29555955). ClinVar contains an entry for this variant (Variation ID: 98546). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003478998 | SCV004222738 | uncertain significance | not specified | 2023-11-01 | criteria provided, single submitter | clinical testing | Variant summary: GUCY2D c.1618C>T (p.Arg540Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250790 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GUCY2D causing Leber Congenital Amaurosis (4.8e-05 vs 0.0022), allowing no conclusion about variant significance. c.1618C>T has been reported in the literature in individuals affected with Leber Congenital Amaurosis (Perrault_2000). This report does not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29555955, 10951519). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Retina International | RCV000084838 | SCV000116974 | not provided | not provided | no assertion provided | not provided |