CONCLUSIONS
There is still a significant limitation in the medical interpretation of genetic testing for complex, non-monogenic phenotypes. Our study shows that almost half of the EFHC1 variants found in patients with GGEs remained as VUS after applying the modified classification proposed in this study using the ACMG/AMP guidelines. In addition, the only variant that could be classified as ‘pathogenic’ (c.685T>C) was found in only 3% of the JME patients in our current study and in 1–5% in the reported literature (Annesi et al., 2007; Podewils, 2015; Raju et al., 2017; Stogmann et al., 2006). Our results, together with previous evidence, indicate that EFHC1 variants are currently best classified as a risk factor—not a causal, major gene—for JME and other GGEs. Given that the interpretation of genetic testing results for EFHC1 variants is complex and offers little information for clinical decision-making, we suggest that the inclusion of EFHC1in gene panels for genetic testing should be limited to research purposes.