Variant: NM_000180.3(GUCY2D):c.389del (p.Pro130Leufs)

CA226143

98602 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: fda950f2-7e0d-45a1-80ed-e0e20e2efa1e

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.3:c.387delC
NM_000180.3:c.389delC
NM_000180.3(GUCY2D):c.389del (p.Pro130Leufs)
NC_000017.11:g.8003436del
CM000679.2:g.8003436del
NC_000017.10:g.7906754del
CM000679.1:g.7906754del
NC_000017.9:g.7847479del
NG_009092.1:g.5767del
ENST00000254854.5:c.389del
ENST00000254854.4:c.389del
NM_000180.3:c.389del
NM_000180.4:c.389del

Pathogenic

• Met criteria codes: PM3 PM2_Supporting PVS1 PP4_Moderate PP1

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.389del (p.Pro130LeufsTer?) variant is a frameshift variant in exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000002639, with 4 alleles / 1515578 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), present at birth (1.0 pt), nystagmus (1.0 pt), extinguished ERG (0.5 pt), photophobia (1 pt) and dyschromatopsia (1 pt). That proband also had clinical exome sequencing performed without any additional potential causative variants identified (4 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID: 37327959, PP4_Moderate). This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 8944027, 10951519). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygotes with variants not yet classified by the LCA/eoRD VCEP and who were not considered for this code. (1 total point, PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 8944027). 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, PP1, PM3, PP4_Moderate, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• PM3: This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 8944027, 10951519). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygotes with variants not yet classified by the LCA/eoRD VCEP and who were not considered for this code. 1 total point, PM3.
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000002639, with 4 alleles / 1515578 total alleles, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).
• PVS1: This is a frameshift variant that introduces a premature stop codon into exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), present at birth (1.0 pt), nystagmus (1.0 pt), extinguished ERG (0.5 pt), photophobia (1 pt) and dyschromatopsia (1 pt). Proband GUCY2D-21 also had clinical exome sequencing performed without any additional potential causative variants identified (4 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID: 37327959, PP4_Moderate).
• PP1: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PP1; PMID: 8944027).