Submission Details

GUCA1A was first reported in relation to autosomal dominant cone dystrophy in 1998 (Payne et al., PMID: 9425234). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern or phenotypic variability between cone dystrophy and cone-rod dystrophy patients who carry pathogenic GUCA1A mutations. Therefore, the following disease entities have been lumped into a single disease entity: [cone dystrophy] (OMIM: 602093) and [cone-rod dystrophy] (OMIM: 602093). The resulting lumped disease entity has been named GUCA1A-related retinopathy.

Twelve missense variants that have been reported in twelve probands in eight publications (PMIDs: 28125083, 24024198, 15953638, 9425234, 19459154, 18706439, 15790869 and 30622141) are included in this curation. Six families were scored for segregation evidence (PMIDs: 28125083, 24024198, 15953638, 9425234, 19459154). The mechanism of pathogenicity appears to be gain-of-function.

This gene-disease association is also supported by RNA and protein expression data from ProteinAtlas showing that GUCA1A is highly and specifically expressed only in the retina, supporting the role of altered GUCA1A function in the development of retinal dystrophy (PMID: 25613900). Co-expression of RetGCI and GUCA1A in HEK293 cells show that GUCA1A functions biochemically as an activator of GUCY2D / RetGC1 and collaborates with it to produce cGMP (PMID: 18541533). Immunoprecipitation assays also show an association between GUCA1A and RD3, a gene that was found by the Retina GCEP to be Definitely associated with a similar retinopathy. A knock-in mouse model introducing the E155G mutation, suspected to be pathogenic in human cone dystrophy patients, was also scored. The authors were able to demonstrate that mice heterozygous for this mutation recapitulate many of the features seen in human patients carrying pathogenic GUCA1A mutations including decreased cone and rod ERG responses, and photoreceptor degeneration (PMID: 21464903). Another mouse model, using mice heterozygous for the L151F mutation in GUCA1A, demonstrates that mutant mice exhibit a reduction in ONL thickness, decreased ERG response, and diminished visual acuity compared to wild-type mice (PMID: 23472098).

In summary, GUCA1A is Definitively associated with autosomal dominant GUCA1A-related retinopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Retina GCEP on May 1, 2025 (SOP Version 9).