Variant: NM_000180.4(GUCY2D):c.61T>C (p.Trp21Arg)

CA145844

92581 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: e87d9cbf-31c0-4658-8610-7a5c1b598ce2

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.61T>C
NM_000180.4(GUCY2D):c.61T>C (p.Trp21Arg)
NC_000017.11:g.8003108T>C
CM000679.2:g.8003108T>C
NC_000017.10:g.7906426T>C
CM000679.1:g.7906426T>C
NC_000017.9:g.7847151T>C
NG_009092.1:g.5439T>C
ENST00000254854.5:c.61T>C
ENST00000254854.4:c.61T>C
NM_000180.3:c.61T>C

Benign

• Met criteria codes: BS2 BP4 BA1

• Not Met criteria codes: BS3

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.61T>C (p.Trp21Arg) variant is a missense variant predicted to replace the tryptophan at position p.21 with arginine. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.2550, with 18,276 alleles / 70,794 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.016 (BA1). This variant has been found in the homozygous state in 3,593 adult individuals in gnomAD v4.1.0, which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.141, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RetGC-1 protein function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). The variant exhibited ~100% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA/eoRD VCEP BS3_Supporting threshold of >50% activity, indicating that it does not trigger a severe defect in protein function, however, it lies in the signal peptide and may be considered ineligible for PS3 or BS3 due to incompatibility with in vitro activity assays (PMID: 11328726, Figure 1). 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: BA1, BS2, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BS2: This variant has been found in the homozygous state in 3,593 adult individuals in gnomAD v.4.1.0, which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2)
• BP4: The computational predictor REVEL gives a score of 0.141, which is below the ClinGen LCA / eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on RETGC-1 function. In addition, the splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate).
• BA1: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.2550, with 18,276 alleles / 70,794 total alleles in the African / African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.016 (BA1).

Not Met criteria codes

• BS3: The variant exhibited ~100% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD VCEP BS3_Supporting threshold of >50% activity, indicating that it does not trigger a severe defect in protein function, however, it lies in the signal peptide and may be considered ineligible for PS3 or BS3 due to incompatibility with in vitro activity assays (PMID: 11328726, Figure 1).