Variant: NM_000180.4(GUCY2D):c.74C>T (p.Ser25Phe)

CA8365468

444397 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: f8920e1a-e792-4711-a501-08dafbc7c510

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.74C>T
NM_000180.4(GUCY2D):c.74C>T (p.Ser25Phe)
NC_000017.11:g.8003121C>T
CM000679.2:g.8003121C>T
NC_000017.10:g.7906439C>T
CM000679.1:g.7906439C>T
NC_000017.9:g.7847164C>T
NG_009092.1:g.5452C>T
ENST00000254854.5:c.74C>T
ENST00000254854.4:c.74C>T
NM_000180.3:c.74C>T

Benign

• Met criteria codes: BS2 BS1 BP4

• Not Met criteria codes: BP2

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.74C>T (p.Ser25Phe) variant is expected to replace the serine at position p.25 with phenylalanine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.004327, with 5044 alleles / 1138600 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 8 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.146, 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 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). This variant has been reported in a proband with early-onset severe retinal dystrophy in the heterozygous state, either in cis or in trans with the NM_000180.4(GUCY2D):c.2516C>G (p.Thr839Arg) variant, which has been previously reported in association with GUCY2D-related dominant retinopathy (PMID: 35205358). Since the carrier status of this variant in a patient with an alternative cause of disease does not support or refute the evidence that this variant may cause disease, the BP2 code is not met. 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, 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 8 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2)
• BS1: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.004327, with 5044 alleles / 1138600 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1).
• BP4: The computational predictor REVEL gives a score of 0.146, 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 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate).

Not Met criteria codes

• BP2: This variant has been reported in a proband with early-onset severe retinal dystrophy in the heterozygous state, either in cis or in trans with the NM_000180.4(GUCY2D):c.2516C>G (p.Thr839Arg) variant, which has been previously reported in association with GUCY2D-related dominant retinopathy (PMID: 35205358). Since the carrier status of this variant in a patient with an alternative cause of disease does not support or refute the evidence that this variant may cause disease, the BP2 code is not met.