Variant: NM_000180.4(GUCY2D):c.369C>T (p.Gly123=)

CA241302

195031 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: d3c44132-b64a-4505-b76b-0c38d144d384

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.369C>T
NM_000180.4(GUCY2D):c.369C>T (p.Gly123=)
NC_000017.11:g.8003416C>T
CM000679.2:g.8003416C>T
NC_000017.10:g.7906734C>T
CM000679.1:g.7906734C>T
NC_000017.9:g.7847459C>T
NG_009092.1:g.5747C>T
ENST00000254854.5:c.369C>T
ENST00000254854.4:c.369C>T
NM_000180.3:c.369C>T

Benign

• Met criteria codes: BS2_Supporting BS1 BP7 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.369C>T (p.Gly123=) variant is silent and occurs outside of the donor and acceptor splice regions. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001777, with 2088 alleles / 1133038 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥3 (gnomAD v4.1.0; BS2_Supporting). 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, BP7). 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: BS1, BS2_Supporting, BP4, BP7.(VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BS2_Supporting: This variant has been found in the homozygous state in 4 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥ 3 (gnomAD version 4.1.0; BS2_supporting).
• BS1: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.001777, with 2088 alleles / 1133038 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1).
• BP7: 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, BP7).
• BP4: 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).