Variant: NM_000180.4(GUCY2D):c.3G>A (p.Met1Ile)

CA226144

98603 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: d48d32b0-171f-48e3-a8f3-91a9f84a5d9a

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.3G>A
NM_000180.4(GUCY2D):c.3G>A (p.Met1Ile)
NC_000017.11:g.8003050G>A
CM000679.2:g.8003050G>A
NC_000017.10:g.7906368G>A
CM000679.1:g.7906368G>A
NC_000017.9:g.7847093G>A
NG_009092.1:g.5381G>A
ENST00000254854.5:c.3G>A
ENST00000254854.4:c.3G>A
NM_000180.3:c.3G>A

Pathogenic

• Met criteria codes: PP4 PVS1 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

The NM_000180.4(GUCY2D):c.3G>A variant is predicted to change the initiation codon (p.Met1) to a stop codon, with no known alternative start codons present (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_supporting). This variant has been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (0.5 points each), PMIDs: 37327959, 10951519). (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), severe visual loss present at birth (1 pt), congenital nystagmus (1 pt), photophobia (1 pt), dyschromatopsia (1 pt), and nonrecordable ERG (0.5 pts) which together are specific for GUCY2D-related recessive retinopathy (total of 5 points, PMID: 37327959, PP4). In summary, this variant meets the criteria to be classified as Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1, PM2_supporting, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), severe visual loss present at birth (1 pt), congenital nystagmus (1 pt), photophobia (1 pt), dyschromatopsia (1 pt), and nonrecordable ERG (0.5 pts) which together are specific for GUCY2D-related recessive retinopathy (total of 5 points, PMID: 37327959, PP4)
• PVS1: Change to initiation codon with no known alternative start codons.
• PM3: This variant has been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (0.5 points each), PMIDs: 37327959, 10951519). (1 total points, PM3).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).