Variant: NM_000180.4(GUCY2D):c.2917G>T (p.Val973Leu)

CA8366252

744554 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 23ae3a77-3a1a-43d3-8dd9-9c22c2768882

Approved on: 2025-01-31

Published on: 2025-01-31

HGVS expressions

NM_000180.4:c.2917G>T
NM_000180.4(GUCY2D):c.2917G>T (p.Val973Leu)
NC_000017.11:g.8015475G>T
CM000679.2:g.8015475G>T
NC_000017.10:g.7918793G>T
CM000679.1:g.7918793G>T
NC_000017.9:g.7859518G>T
NG_009092.1:g.17806G>T
ENST00000254854.5:c.2917G>T
ENST00000254854.4:c.2917G>T
NM_000180.3:c.2917G>T

Likely Benign

• Met criteria codes: BS2_Supporting BS1

• Not Met criteria codes: PP3 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.2917G>T (p.Val973Leu) variant is predicted to replace the valine at position p.973 with leucine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0006200, with 1000 alleles / 1612860 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. The LCA/eoRD VCEP chose to use the population frequency in the Finnish population over the Grpmax frequency to meet the BS1 criteria - with a frequency of 0.01376 with 877 alleles / 63722 total alleles in the Finnish population, the BS1 cutoff >0.0016 is significantly exceeded (BS1). This variant has been found in the homozygous state in 3 adult individuals in gnomAD (gnomAD version 4.1.1; BS2_supporting). The computational predictor REVEL gives a score of 0.51, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 for PP3 and above the threshold of <0.290 for BP4. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which predicts a low or indeterminate impact on splicing. Neither PP3 nor BP4 is met. In summary, this variant meets the criteria to be classified as Likely Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2_Supporting. (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 3 adult individuals in gnomAD (gnomAD version 4.1.1; BS2_supporting).
• BS1: This variant is present in gnomAD v.4.1.0 at a frequency of 0.01376 with 877 alleles / 63722 total alleles in the Finnish population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1).

Not Met criteria codes

• PP3: The computational predictor REVEL gives a score of 0.51, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.1, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.
• BP4: The computational predictor REVEL gives a score of 0.51, which is above the ClinGen LCA / eoRD VCEP threshold of <0.290 and does not predict a non-damaging effect on RETGC-1 function. The splicing impact predictor SpliceAI gives a delta score of 0.10 which is at the ClinGen LCA / eoRD VCEP threshold of <0.1 and represents an intermediate prediction of impact on GUCY2D splicing.