Variant: NM_000180.4(GUCY2D):c.2345T>A (p.Leu782His)

CA8366093

255475 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 3afb1b38-5bad-4aad-9385-32de8d83654c

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.2345T>A
NM_000180.4(GUCY2D):c.2345T>A (p.Leu782His)
NC_000017.11:g.8013961T>A
CM000679.2:g.8013961T>A
NC_000017.10:g.7917279T>A
CM000679.1:g.7917279T>A
NC_000017.9:g.7858004T>A
NG_009092.1:g.16292T>A
ENST00000254854.5:c.2345T>A
ENST00000254854.4:c.2345T>A
NM_000180.3:c.2345T>A

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.2345T>A (p.Leu782His) variant is predicted to change the leucine at position p.782 to histidine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.3995, with 30227 alleles / 74954 total alleles in the African/African American 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 17920 adult individuals in gnomAD (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.119, 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 0.01, 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 0.3995, with 30227 alleles / 74954 total alleles in the African/African American 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 17920 adult individuals in gnomAD (gnomAD version; BS2).
• BP4: The computational predictor REVEL gives a score of 0.119, 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 0.01, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate).