Prevalence of Risk Variants for Glaucoma in the MYOC gene in the General Population

Purpose To assess the clinical relevance of myocilin ( MYOC) gene variants reported in association with glaucoma in the literature, and to estimate the prevalence of these variants in different populations. Methods We reviewed the literature for published MYOC variants in glaucoma patients and estimated their prevalence in the general population using the gnomAD and BRAVO databases. We used several bioinformatics tools and the criteria of the American College of Medical Genetics and Genomics (ACMG) to assess the pathogenicity of the variants. We evaluated the carrier frequency of likely pathogenic and risk variants in gnomAD, including its subpopulations. Results We found 13 reported missense and 5 loss‐of‐function (LOF) variants in MYOC that were both likely pathogenic or risk variants and listed in the gnomAD database. Six likely pathogenic missense variants were p.Gly399Val (c.1196G>T), p.Thr377Met (c.1130C>T), p.Thr353Ile (c.1058C>T), p.Gly326Ser (c.976G>A), p.Gln48His (c.144G>T), and p.Cys25Arg (c.73T>C). They were most prevalent in East and South Asia (frequency, 0.0092 and 0.0081, respectively). The most common missense variants were p.Thr353Ile (0.0091 in East Asia) and p.Gln48His (0.0079 in South Asia). Five LOF variants were p.Gln368Ter (c.1102C>T), p.Arg272Ter (c.814C>T), p.Arg91Ter (c.271C>T), p.Arg46Ter (c.136C>T) and p.Tyr453MetfsTer11 (c.1357delT). We considered these glaucoma risk variants. They were most prevalent in the East Asian and the Finnish population (0.0093 and 0.0033, respectively). Conclusions Pathogenic MYOC variants appear to be population‐associated. Likely pathogenic missense variants seem to be most prevalent in Asia. The glaucoma risk variant p.Gln368Ter is most common in the European population with the highest prevalence in the Finnish population. Our results highlight allelic heterogeneity of MYOC variants in open‐angle glaucoma.