Variant: NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser)

CA145842

9353 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 00fffd1e-b768-44b9-81ae-111306beb5bf

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.154G>T
NM_000180.4(GUCY2D):c.154G>T (p.Ala52Ser)
NC_000017.11:g.8003201G>T
CM000679.2:g.8003201G>T
NC_000017.10:g.7906519G>T
CM000679.1:g.7906519G>T
NC_000017.9:g.7847244G>T
NG_009092.1:g.5532G>T
ENST00000254854.5:c.154G>T
ENST00000254854.4:c.154G>T
NM_000180.3:c.154G>T

Benign

• Met criteria codes: BA1 BS2 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.154G>T (p.Ala52Ser) variant is predicted to replace the alanine at position p.52 with serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 95,479 adult individuals in gnomAD v4.1.0 (BS2). The computational predictor REVEL gives a score of 0.126, 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). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BA1: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.6857, with 26306 alleles / 37974 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1).
• BS2: This variant has been found in the homozygous state in 95,479 adult individuals in gnomAD (gnomAD v4.1.0; BS2).
• BP4: The computational predictor REVEL gives a score of 0.126, 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).