Variant: NM_000180.4(GUCY2D):c.164C>T (p.Thr55Met)

CA232809

143061 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 756ab94c-c8ea-44a0-8617-cd769e850c35

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.164C>T
NM_000180.4(GUCY2D):c.164C>T (p.Thr55Met)
NC_000017.11:g.8003211C>T
CM000679.2:g.8003211C>T
NC_000017.10:g.7906529C>T
CM000679.1:g.7906529C>T
NC_000017.9:g.7847254C>T
NG_009092.1:g.5542C>T
ENST00000254854.5:c.164C>T
ENST00000254854.4:c.164C>T
NM_000180.3:c.164C>T

Likely Benign

• Met criteria codes: BS1 BS2_Supporting

• Not Met criteria codes: BP4 PP3

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.164C>T (p.Thr55Met) variant is predicted to replace the threonine at position p.55 with methionine. This variant is present in gnomAD v4.1.0 at a Grpmax allele frequency of 0.008088, with 341 alleles / 38476 total alleles in the East Asian 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 3 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥3 (gnomAD version 4.1.0; BS2_supporting). In addition, the reported frequency of this variant in the Vietnamese population is 1.5%. (PMID:31180159). The computational predictor REVEL gives a score of 0.409, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on GUCY2D function. Additionally, the splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. Several papers describing East Asian IRD cohorts (PMIDs: 21602930, 23847139) report the presence of the variant in patients but since this is the population with the highest reported allele frequency these papers were not counted toward PM3. 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. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BS1: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.008088, with 341 alleles / 38476 total alleles in the East Asian population (including 3 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0016 (BS1). In addition, the reported frequency of this variant in the Vietnamese population is 1.5%. (PMID:31180159)
• BS2_Supporting: This variant has been found in the homozygous state in 3 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥3 (gnomAD version 4.1.0; BS2_supporting).

Not Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.409, which is above the ClinGen LCA / eoRD VCEP threshold of <0.290 and does not predict a non-damaging effect on GUCY2D function.
• PP3: The computational predictor REVEL gives a score of 0.409, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on GUCY2D function. Additionally, the splicing impact predictor SpliceAI gives a score of 0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.