Variant: NM_000180.4(GUCY2D):c.2384G>A (p.Arg795Gln)

CA8366103

596790 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 39beaa0e-090f-46c1-954f-5ada54523548

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.2384G>A
NM_000180.4(GUCY2D):c.2384G>A (p.Arg795Gln)
NC_000017.11:g.8014000G>A
CM000679.2:g.8014000G>A
NC_000017.10:g.7917318G>A
CM000679.1:g.7917318G>A
NC_000017.9:g.7858043G>A
NG_009092.1:g.16331G>A
ENST00000254854.5:c.2384G>A
ENST00000254854.4:c.2384G>A
NM_000180.3:c.2384G>A

Likely Pathogenic

• Met criteria codes: PP1_Moderate PP3_Moderate PP4_Moderate PM3 PM2_Supporting

Expert Panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GUCY2D Version 1.0.0

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_000180.4(GUCY2D):c.2384G>A (p.Arg795Gln) is a missense variant that replaces arginine with glutamine at position p.795. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000009916, with 16 alleles / 1,613,582 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 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 total point, PMIDs: 17724218, 31630094, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 26352687). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts) with onset at age 7 months (1 pt), genotyping by targeted exome sequencing without identification of another cause of retinal disease (2 pts), extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), photophobia (1 pt), and no visual acuity (1 pt), which together are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 31630094, PP4_Moderate). The computational predictor REVEL gives a score of 0.83, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC1 protein function (PP3_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, PP3_Moderate, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• PP1_Moderate: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 26352687).
• PP3_Moderate: The computational predictor REVEL gives a score of 0.83, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC function (PP3_Moderate).
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of LCA (0.5 pts), with onset at age 7 months (1 pt). Both rod and cone ERGs were extinguished (0.5+1.0 pts) and patient had nystagmus (1 pt), photophobia (1 pt), and no visual acuity (1 pt). Patient underwent targeted exome sequencing without identification of another likely cause (2 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 31630094, PP4_Moderate).
• PM3: This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 17724218, 26352687, 31630094, 39761966). (1 total point, PM3).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000009916, with 16 alleles / 1,613,582 total alleles, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).