Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000180.4:c.3020C>A

CA397955377

Gene: GUCY2D (HGNC:3000)

Condition: GUCY2D-related recessive retinopathy (MONDO:0100453)

Inheritance Mode: Autosomal recessive inheritance

UUID: ced8a8d3-e681-484a-a99e-c962e047c599

Approved on: 2025-12-19

Published on: 2025-12-19

HGVS expressions

NM_000180.4:c.3020C>A

NC_000017.11:g.8015818C>A

CM000679.2:g.8015818C>A

NC_000017.10:g.7919136C>A

CM000679.1:g.7919136C>A

NC_000017.9:g.7859861C>A

NG_009092.1:g.18149C>A

ENST00000254854.5:c.3020C>A

ENST00000254854.4:c.3020C>A

NM_000180.3:c.3020C>A

Likely Pathogenic

PM2_Supporting PVS1

PP4 PM3

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_000180.4(GUCY2D):c.3020C>A (p.Ser1007Ter) is a nonsense variant that introduces a premature stop codon into exon 18 of 20 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000006202, with 1 allele / 1,612,284 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.982G>C (p.Ala328Pro) variant confirmed in trans (VCEP member-provided data) but has not been counted for PM3 to avoid circularity. The proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by next-generation sequencing panel that did not identify an alternative basis for disease (2 pts), which are not sufficiently specific for GUCY2D-related recessive retinopathy to meet the PP4 code (total 2.5 points, VCEP member-provided data). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PVS1 and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025).

PM2_Supporting

This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0000006202, with 1 allele / 1,612,284 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting).

PVS1

This is a nonsense variant that introduces a premature stop codon into exon 18 of 20 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1).

PP4

At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with genotyping by next-generation sequencing panel that did not identify an alternative basis for disease (2 pts), which are not sufficiently specific for GUCY2D-related recessive retinopathy to meet the PP4 code (total 2.5 points, VCEP member-provided data).

PM3

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000180.4(GUCY2D):c.982G>C (p.Ala328Pro) variant confirmed in trans (VCEP member-provided data) but has not been counted for PM3 to avoid circularity.

Curation History

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