Submission Details

BEST1 (also referred to in the literature as VMD2 or TU15B) was first reported in relation to autosomal dominant inheritance of Best vitelliform macular dystrophy (BVMD) in 1998 (Petrukhin et al., PMID: 9662395). Disease-causing BEST1 mutations are also associated with autosomal dominant vitreoretinochoroidopathy (ADVIRC) and autosomal recessive bestrophinopathy (ARB). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the phenotype of cases diagnosed with vitelliform macular dytrophy or other forms of BEST1-related dominant retinopathy has been found to represent a distinct disease entity from cases diagnosed with vitreoretinochoroidopathy (AD) or bestrophinopathy (AR). Therefore, this curation has focused on BEST1-related dominant retinopathy, while the gene will undergo separate curations for BEST1-related vitreoretinochoroidopathy and BEST1-related recessive retinopathy.

This curation has included twenty variants (17 missense, 1 in-frame deletion, 1 nonsense and 1 frameshift) that have been reported in twenty probands in nine publications (PMIDs: 10331951, 16754206, 9700209, 10617923, 14517959, 27193166, 10854112, 25082885, 31836750). Segregation data have also been scored from three families showing co-segregation of BEST1 with BVMD (PMID: 10617923, PMID: 9700209, PMID: 16754206). The mechanism of pathogenicity appears to be dominant negative, primarily through mislocalization of the BEST1 protein and a reduction in anion conductance in the RPE.

This gene-disease association is also supported by experimental evidence that BEST1 mRNA and BEST1 protein expression are restricted to the RPE layer of the retina (PMID: 9700209 and PMID: 29022597). Two functional alteration experiments, one conducted in patient cells and one conducted in HEK-293 cells, show that BEST1 mutations result in mislocalization of the mature protein in the cell and strongly reduced anion permeability (PMID: 21878505, PMID: 32111077). A BEST1 (+/W93C) knock-in mouse model was shown to recapitulate many of the features of BVMD seen in human patients, including an abnormal LP luminance-response function, accumulation of lipofuscin in RPE cells, and the formation of fluid- and debris-filled retinal detachments (PMID: 20053664).

In summary, BEST1 is definitively associated with BEST1-related dominant retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina GCEP on August 3rd, 2023 (SOP Version 9).