Variant: NM_000180.4(GUCY2D):c.271G>C (p.Ala91Pro)

CA241298

195029 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 45079f94-071a-407c-8468-3e84d2fe1a39

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.271G>C
NM_000180.4(GUCY2D):c.271G>C (p.Ala91Pro)
NC_000017.11:g.8003318G>C
CM000679.2:g.8003318G>C
NC_000017.10:g.7906636G>C
CM000679.1:g.7906636G>C
NC_000017.9:g.7847361G>C
NG_009092.1:g.5649G>C
ENST00000254854.5:c.271G>C
ENST00000254854.4:c.271G>C
NM_000180.3:c.271G>C

Benign

• Met criteria codes: BP4 BS2 BS1

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.271G>C (p.Ala91Pro) variant is predicted to substitute the alanine at position p.91 with proline. This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.006915, with 581/78368 total alleles in the South Asian population, which is within the ClinGen LCA/eoRD VCEP BS1 range of 0.0016 - 0.016 (BS1). This variant has also been found in the homozygous state in 6 adult individuals in gnomAD which meets the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2) The computational predictor REVEL gives a score of 0.219, which is below the ClinGen LCA/eoRD VCEP threshold of <0.290 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, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). 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. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BP4: The computational predictor REVEL gives a score of 0.219, which is below the ClinGen LCA / eoRD VCEP threshold of <0.290 and predicts a non-damaging effect on RetGC-1 function. In addition, 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).
• BS2: This variant has been found in the homozygous state in 6 adult individuals in gnomAD which meets 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 0.006915, with 581/78368 total alleles in the South Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of between 0.016 - 0.0016 (BS1).