Variant: NM_000180.4(GUCY2D):c.1236C>T (p.Asp412=)

CA226041

98539 (ClinVar)

Gene: GUCY2D

Condition: GUCY2D-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 45f6975c-bff9-4f3a-a3d7-620d7df1e15e

Approved on: 2025-01-30

Published on: 2025-01-30

HGVS expressions

NM_000180.4:c.1236C>T
NM_000180.4(GUCY2D):c.1236C>T (p.Asp412=)
NC_000017.11:g.8006572C>T
CM000679.2:g.8006572C>T
NC_000017.10:g.7909890C>T
CM000679.1:g.7909890C>T
NC_000017.9:g.7850615C>T
NG_009092.1:g.8903C>T
ENST00000254854.5:c.1236C>T
ENST00000254854.4:c.1236C>T
NM_000180.3:c.1236C>T

Likely Benign

• Met criteria codes: BP7 BP4

• Not Met criteria codes: BS1 PM2

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

NM_000180.4(GUCY2D):c.1236C>T (p.Asp412=) is a synonymous variant in exon 4 of 20. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.001028 with 1659 alleles / 1,613,498 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion. This variant has a Grpmax allele frequency of 0.001233, with 1519 alleles / 1180008 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion as well. The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). 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: BP4, BP7. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

Met criteria codes

• BP7: The splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP7).
• BP4: The computational predictor REVEL has no data as this is a synonymous variant. The splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).

Not Met criteria codes

• BS1: This variant is present in gnomAD v.4.1.0 at a Grpmax frequency of 0.001233 with 1519 alleles / 1180008 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 and fails to meet this criterion.
• PM2: This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.001028 with 1659 alleles / 1,613,498 total alleles, which is higher than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 and fails to meet this criterion.