Variant: NM_000180.4(GUCY2D):c.1315G>A (p.Gly439Arg)

CA8365708

374028 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 81efc62b-bd2d-4157-bc26-b491ce88b314

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.1315G>A
NM_000180.4(GUCY2D):c.1315G>A (p.Gly439Arg)
NC_000017.11:g.8006651G>A
CM000679.2:g.8006651G>A
NC_000017.10:g.7909969G>A
CM000679.1:g.7909969G>A
NC_000017.9:g.7850694G>A
NG_009092.1:g.8982G>A
ENST00000254854.5:c.1315G>A
ENST00000254854.4:c.1315G>A
NM_000180.3:c.1315G>A

Likely Benign

• Met criteria codes: BS2_Supporting BS1

• Not Met criteria codes: PP3

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

The NM_000180.4(GUCY2D):c.1315G>A (p.Gly439Arg) variant is predicted to replace the glycine at position p.439 with arginine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001850 with 190 alleles / 90756 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥ 3 (gnomAD version 4.1.0; BS2_supporting). In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2_supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025)

Met criteria codes

• BS2_Supporting: This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥ 3 (gnomAD version 4.1.0; BS2_supporting).
• BS1: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001850 with 190 alleles / 90756 total alleles in the South Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.459, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.