Submission Details

The PROM1 gene was first reported in relation to autosomal dominant retinal degeneration in 2008 (PMID: 18654668). The phenotypic spectrum includes the following clinical diagnoses: STGD4 (Stargardt Disease-4) characterized by macular dystrophy, yellow fundus flecks, and dark choroid pattern (PMID: 10420191); autosomal dominant MCDR2 (retinal macular dystophy-2 ) characterized by retinal pigment epithelium atrophy, bull's-eye macular dystrophy, visual impairment, central scotomata, and age-related rod and cone abnormalities (PMID: 12657606); autosomal dominant cone-rod dystrophy characterized by both cone and rod photoreceptor degeneration (PMID: 18654668). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, dominant cases were compared with cases of PROM1-related recessive retinopathy, which includes cone-rod dystrophy 12 and retinitis pigmentosa 41. The recessive disease is more severe with earlier onset, and is associated with null or close to null PROM1 function. The dominant disease is associated with milder phenotypes, and has a late adulthood age onset. It is associated with missense variants and thought to arise via a dominant negative mechanism. Due to the distinct underlying molecular mechanisms of the two disease forms, dominant cases were split from the recessive cases and were collectively curated under PROM1-related dominant retinopathy.

Four suspected disease-causing missense variants were scored as part of this curation, which have been collectively reported in twelve probands in nine publications (PMID: 18654668, PMID: 10205271, PMID: 12657606, PMID: 38072963, PMID: 20393116, PMID: 28840994, PMID: 31576780, PMID: 29416601, PMID: 28095140). All except three probands harbor the p.Arg373Cys variant. Three large families with distinct disease haplotypes showed strong evidence of co-segregation of the genotype with affected status (PMID: 18654668). The literature included more case-level and co-segregation evidence, but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence.

This gene-disease association is also supported by experimental evidence indicating that degeneration of the photoreceptor layer may be the shared defect underlying PROM1-related disease. PROM1 is specifically expressed in retinal tissues (PMID: 30239781) and the protein product localizes particularly to the discs at the base of the photoreceptor cell outer segments (PMID: 18654668, PMID: 10587575). This localization is consistent with the known association of PROM1 with membrane protrusions (PMID: 10681530) and its proposed function in cell membrane homeostasis by regulating formation of extracellular vesicles (PMID: 39168849). PROM1 is an integral membrane protein that associates with cholesterol, and mutations in cholesterol binding domains affect membrane homeostasis in cultured mammalian cells. The cadherin family member CDHR1 gene product co-immunoprecipitates with PROM1 (PMID: 18654668), and harbors variants associated with cone-rod dystrophy 15 (PMID: 20805371), retinal macular dystrophy (PMID: 28765526), and retinitis pigmentosa 65 (PMID: 20087419). A transgenic mouse expressing the dominant PROM1 p.Arg373Cys variant showed similar phenotypes observed in human STGD4 and MCDR2 cases; the mutant mouse retina showed disorganized outer segment disc membranes and mislocalized PROM1, supporting the role of PROM1 in membrane organization in photoreceptors.

In summary, PROM1 is definitively associated with PROM1-related dominant retinopathy. This has been demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on October 3rd, 2024 (SOP Version 10).