Variant: NM_000180.4(GUCY2D):c.1721G>A (p.Arg574His)

CA8365861

493206 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 6c381b73-eb5c-4b00-9287-bdab840efceb

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.1721G>A
NM_000180.4(GUCY2D):c.1721G>A (p.Arg574His)
NC_000017.11:g.8009558G>A
CM000679.2:g.8009558G>A
NC_000017.10:g.7912876G>A
CM000679.1:g.7912876G>A
NC_000017.9:g.7853601G>A
NG_009092.1:g.11889G>A
ENST00000254854.5:c.1721G>A
ENST00000254854.4:c.1721G>A
NM_000180.3:c.1721G>A

Likely Benign

• Met criteria codes: BP4

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.1721G>A (p.Arg574His) variant is predicted to replace the arginine at position p.574 with histidine. The computational predictor REVEL gives a score of 0.182, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RETGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.00005950, with 96 alleles / 1,613,430 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 but is not considered due to the evidence supporting a benign classification. 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: BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.182, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RETGC-1 function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate).