Christensen et al conludes: “15% of Danish ARVC/D patients have mutations in PKP2. Our finding of previously reported disease-causing missense mutations in healthy controls raises concerns about the pathogeneity of these mutations and suggests increased susceptibility or a disease-modifying role. We recommend conservative evaluation of missense variants in ARVC/D patients, functional characterization and large-scale sequencing of healthy controls to clarify normal variation in PKP2.”
The combined case-control data from several papers reaches, at best, a p-value of 0.046. This is almost certainly biased to overrepresent the variant in cases, however, as only papers which detected S140F in their patient screens are included in this sum. Note that this p-value is actually worse than that found by Christensen et al., and those authors are cautious regarding evaluating this variant as pathogenic.
Note: This is a very rough calculation for the purposes of assigning penetrance in our evaluation, the significance for this variant is quite weak in the first place. Assuming it is real, and ARVD/C has an incidence of 1 in 10,000 in the general population (.01%), these case/control numbers suggest 0.025% attributable increased risk. Using the numbers from Christensen et al. alone implies a .06% increased attributable risk.