Submission Details

EFHC1 was first reported in relation to autosomal dominant epilepsy in 2004 with five different missense variants identified in probands from six unrelated families (Suzuki et al, PMID: 15258581). Numerous additional probands with epilepsy have been reported to have variants in EFHC1 (PMIDs: 17634063, 22690745, 22727576, 16839746, 17159113, 15258581). However, many of these variants are observed in population databases at frequencies too high to be considered pathogenic, with minor allele frequencies (MAF) of 2.857e-5 to 0.05973. Functional studies do not provide a consistent mechanism of disease. In summary, the evidence supporting the relationship between EFHC1 and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim.

This gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on June 18, 2018. It was reevaluated on September 5, 2023. As a result of this reevaluation, the classification changed from Disputed to Refuted. Since 2018, there have been additional individuals reported with epilepsy and variants in EFHC1. However, these variants are found in gnomAD at high allele frequencies, or do not have convincing segregation or functional evidence to support this gene-disease relationship (PMID: 18505993, 33969125, 36842888). Additionally, a recent publication compared the frequency of ultra rare EFHC1 variants in over 15,000 patients and approximately 11,000 controls. The authors determined that the frequency of variants in EFHC1 did not differ between patients and controls (PMID: 31056551). This evidence, in combination with the lack of case-level evidence to support this gene-disease relationship, has led the Epilepsy GCEP to refute the relationship between autosomal dominant epilepsy and EFHC1.