PROM1

Inheritance Pattern: AD

Disease ID:MONDO:0019353

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012796

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:1040053

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:1040053

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0012796

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0011957

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:1040052

Submitter: ClinGen

The *PROM1* gene was first reported in relation to autosomal recessive retinal degeneration in 2000 (PMID: 10587575). Subsequent publications expanded the phenotypic spectrum associated with homozygous or compound heterozygous *PROM1* variants to include diverse diagnoses such as retinitis pigmentosa 41 (PMID: 17605048) and cone-rod dystrophy 12 (PMID: 24474277). These cases typically have onset in childhood or adolescence and exhibit a wide variety of retinal features ranging from macular degeneration, progressive reduction in visual acuity, and central scotoma to night blindness, peripheral visual field loss, retinal blood vessel attenuation, and optic disc pallor. Electroretinogram responses are generally decreased in amplitude or undetectable, particularly from cones. Degeneration of the retinal pigment epithelium in the macula is often observed and may be described as bull’s eye maculopathy. Optical coherence tomography images generally show retinal thinning and particularly loss of the photoreceptor layer. The spectrum of disease also includes cases with heterozygous *PROM1* variants diagnosed as cone-rod dystrophy 12 (PMID: 35947379), Stargardt-like macular dystrophy (PMID: 29416601), or retinal macular dystrophy type 2 (PMID: 18654668). These heterozygous cases exhibit relatively later onset but a similar range of phenotypes that can include reduced visual acuity, bull's-eye macular dystrophy, progressive macular atrophy, color vision abnormalities, and night blindness. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, recessive cases of cone-rod dystrophy or retinitis pigmentosa were compared with dominant cases of cone-rod dystrophy, retinal macular dystrophy, or Stargardt-like maculopathy. The shared mode of inheritance, molecular mechanism (biallelic loss-of-function) and phenotypic overlap among recessive cases motivated cone-rod dystrophy 12 and retinitis pigmentosa 41 to be combined into a single gene curation, with the lumped disease entity referred to as PROM1-related recessive retinopathy. On the other hand, cases with overlapping phenotypes but a dominant mode of inheritance differed in their molecular mechanism (dominant negative), whereas the recessive families had unaffected heterozygous carriers. Therefore, dominant cases have been lumped into a separate disease entity, referred to as PROM1-related dominant retinopathy. Eight suspected disease-causing variants were scored as part of this curation (three nonsense, three frameshift, one canonical splice site variant, and one non-canonical intronic variant disrupting splicing), which have been collectively reported in six probands in six publications (PMID: 10587575, PMID: 17605048, PMID: 24474277, PMID: 24763286, PMID: 25472526, PMID: 26702251). Four of the probands scored in this curation harbored the variant in the homozygous state, with three reported as consanguineous, while two other probands harbored variants in compound heterozygosity. Two large families with evidence of co-segregation of the genotype with affected status contributed to the scoring of the gene-disease relationship (PMID: 10587575, PMID: 17605048). 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 recessive 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: 10587575, PMID: 18654668). This localization is consistent with the known association of PROM1 with membrane protrusions in general (PMID: 10681530) and its proposed function as an organizer of cell membrane topology in the morphogenesis of the developing photoreceptor cell outer segment disc membrane. The CDHR1 gene product similarly localizes to these structures, 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). Homozygous knockout of the mouse ortholog *Prom1* results in light-dependent degeneration of the photoreceptor and outer nuclear layers, and defective dark-adapted electroretinogram responses (PMID: 25414197). Homozygous deletion of the zebrafish ortholog *Prom1b* results in photoreceptor degeneration, enhanced apoptosis, loss of the outer nuclear layer, and delayed morphogenesis of outer segment discs (PMID: 31362982). In summary, *PROM1* is definitively associated with PROM1-related recessive retinopathy. This has been repeatedly 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 April 4th, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0012796

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011957

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012983

Submitter: Labcorp Genetics (formerly Invitae)