NM_000180.4:c.1956+1G>A

CA8365937

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 655bbcc4-fd36-4286-b8a4-2c1ecebcbf86

Approved on: 2025-01-31

Published on: 2025-01-31

HGVS expressions

NM_000180.4:c.1956+1G>A
NC_000017.11:g.8012351G>A
CM000679.2:g.8012351G>A
NC_000017.10:g.7915669G>A
CM000679.1:g.7915669G>A
NC_000017.9:g.7856394G>A
NG_009092.1:g.14682G>A
ENST00000254854.5:c.1956+1G>A
ENST00000254854.4:c.1956+1G>A
NM_000180.3:c.1956+1G>A

Pathogenic

• Met criteria codes: PP1 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.1956+1G>A variant disrupts a canonical splice site in intron 9 and is predicted to lead to in-frame skipping of a critical exon (PVS1). This variant is present in gnomAD v.4.1.0 at an allele frequency of 6.202e-7, with 1 allele / 1612348 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.1672G>A (p.Asp558Asn) and NM_000180.4(GUCY2D):c.1245del (p.Phe415fs) variants confirmed in trans (1 point, PMID: 32865313), one of which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 1 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 compound heterozygous state (PMID: 32865313, PP1). 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, PM3, and PP1. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• 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 compound heterozygous state (PMID: 32865313, PP1).
• PVS1: This variant disrupts a canonical splice site in intron 9 and is predicted to lead to in-frame skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1).
• PM3: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.1672G>A (p.Asp558Asn) and NM_000180.4(GUCY2D):c.1245del (p.Phe415fs) variants confirmed in trans (1 point, PMID: 32865313), one of which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1 1 point, PM3).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at an allele frequency of 6.202e-7, with 1 allele / 1612348 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).