Variant: NM_000180.4(GUCY2D):c.1052A>G (p.Tyr351Cys)

CA226036

98536 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 86ceb82a-6d6d-483c-a8bf-98c684448d1c

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.1052A>G
NM_000180.4(GUCY2D):c.1052A>G (p.Tyr351Cys)
NC_000017.11:g.8006388A>G
CM000679.2:g.8006388A>G
NC_000017.10:g.7909706A>G
CM000679.1:g.7909706A>G
NC_000017.9:g.7850431A>G
NG_009092.1:g.8719A>G
ENST00000254854.5:c.1052A>G
ENST00000254854.4:c.1052A>G
NM_000180.3:c.1052A>G

Likely Pathogenic

• Met criteria codes: PP3 PM3_Strong PM2_Supporting PS3_Supporting PP4_Moderate

• Not Met criteria codes: PM6

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.1052A>G (p.Tyr351Cys) variant is predicted to replace the tyrosine at position p.351 with cysteine. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000005622, with 9 alleles / 1,600,764 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.733, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC-1 protein function. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 32865313, 15024725). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg1059Ter variant confirmed in trans (did not count, PMID: 27208204), which has not yet been classified by the ClinGen LCA/eoRD VCEP. It has also been reported in another proband with with early-onset severe retinal dystrophy who was compound heterozygous with the c.2943del variant, classified as pathogenic by the VCEP, confirmed in trans (1 point, PMID: 17525851). (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with an age of onset before age 4 (1 pt). Reported to have nystagmus (1 pt), sluggish pupils (0.5 pts), decreased peripheral vision (1 pt), and decreased central visual acuity (1 pt). ERG and multifocal ERG below normal thresholds (1 pt). Fundoscopy and blue autofluorescence unremarkable. Genetic testing using the ASPER Biotech LCA-Microarray (2006) did not reveal any additional likely variants. (2 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 8 points, PMID: 17525851, PP4_Moderate). The protein exhibits a dramatically reduced RD3 signal compared to wild-type control in a GUCY2D pull-down assay. (PS3_Supporting, PMID: 25477517). This variant has been identified as a de novo occurrence in 1 individual with a phenotype specific for GUCY2D-related recessive retinopathy at the PP4_Moderate level (PMID: 17525851). However, the PM6 code was not met since the variant was hypothesized to be on the paternal allele and the genotyping methods were not sufficient to confirm the paternal relationship. In summary, this variant meets the criteria to be classified as likely pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP3, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.733, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and predicts a damaging effect on RetGC function.
• PM3_Strong: This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 32865313, 15024725). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg1059Ter variant confirmed in trans (did not count, PMID: 27208204), which has not yet been classified by the ClinGen LCA / eoRD VCEP. It has also been reported in another proband with with early-onset severe retinal dystrophy who was compound heterozygous with the c.2943del variant, classified as pathogenic by the VCEP, confirmed in trans (1 point, PMID: 17525851). (2 total points, PM3_Strong).
• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000005622, with 9 alleles / 1600764 total alleles, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).
• PS3_Supporting: Dramatically reduced RD3 signal comparable to wild-type control in GUCY2D pull-down.
• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) with an age of onset before age 4 (1 pt). Reported to have nystagmus (1 pt), sluggish pupils (0.5 pts), decreased peripheral vision (1 pt), and decreased central visual acuity (1 pt). ERG and multifocal ERG below normal thresholds (1 pt). Fundoscopy and blue autofluorescence unremarkable. Genetic testing using the ASPER Biotech LCA-Microarray (2006) did not reveal any additional likely variants. (2 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 8] points, PMID: 17525851, PP4_Moderate).

Not Met criteria codes

• PM6: This variant has been identified as a de novo occurrence in 1 individual with a phenotype specific for GUCY2D-related recessive retinopathy at the PP4_Moderate level (PMID: 17525851). However, the PM6 code was not met since the variant was hypothesized to be on the paternal allele and the genotyping methods were not sufficient to confirm the paternal relationship.