A looming problem in implementing genomic medicine in the EHR context is that for the vast majority of non-synonymous genetic sequence variants, currently available tools to predict in vitro or in vivo function are imperfect at best. The development of large databases such as ClinGen that aspire to present not only variant frequency data but also associated phenotypes developed from a range of sources including crowd-sourcing, will help tackle this problem.66 The availability of Mendelian disease gene genotype or sequence data in large numbers of unselected subjects with EHRs may allow estimates of penetrance across populations. The eMERGE Network took this approach in a study of the hemochromatosis-related genotypes (homozygote C282YHFE homozygotes or C282Y/H63E compound heterozygotes) in 538 carriers in a set of 39,000 genotyped subjects.67 The homozygotes were more likely to carry the clinical diagnosis of hereditary hemochromatosis than the compound heterozygotes and as in previous reports men were more likely to carry the diagnosis than women: 24.4% of homozygous men and 14.0% of homozygous women carried the diagnosis. However, the prevalence of liver disease and diabetes were both
