Submission Details

Variants in SCN9A have been observed in individuals with a variety of primarily neuropathy phenotypes, including autosomal dominant small fiber neuropathy and erythermalgia and autosomal recessive congenital insensitivity to pain. A relationship between SCN9A and autosomal dominant epilepsy (MONDO:0005027) has also been reported, which is the focus of this recuration. The SCN9A gene was initially curated by the ClinGen Epilepsy Gene Curation Expert Panel (GCEP) in relation to autosomal dominant epilepsy on 6/5/2018. At the time, this gene-disease relationship was classified as LIMITED based on case-level data. Since that time, a publication providing evidence to refute this gene-disease relationship has become available.
In the initial curation, the primary evidence supporting a gene-disease relationship with epilepsy was provided from Singh et al. 2009 (PMID 19763161). This publication described a large family segregating the p.Asn641Tyr SCN9A variant in individuals with febrile or afebrile seizures, primarily limited to childhood. Additionally, this publication provided weak experimental evidence with a homozygous p.Asn641Tyr knock-in mouse model. A recent publication by Fasham et al. 2020 (PMID 33216760) provides evidence to refute the pathogenicity of the p.Asn641Tyr variant. In this publication, the p.Asn641Tyr variant was identified in an Amish proband with a de novo CHD4 variant, consistent with the proband phenotype; the SCN9A variant was shown to be inherited from the proband’s unaffected father. The p.Asn641Tyr variant was subsequently identified in another 7 Amish families where it was transmitted through an additional minimum 26 constitutive gene carriers and presumed to be transmitted to hundreds of additional offspring, only one of whom had any reported seizures. Additionally, the p.Asn641Tyr variant is present in 6 alleles in the gnomAD database. Additional variants in SCN9A have been reported in the literature in association with epilepsy and are summarized in this recuration, but the majority are unable to be scored due to lack of segregation with disease, high minor allele frequency in general population databases or an alternate molecular explanation for disease. Case level data provides a score of 0.4 points and there is no scored experimental evidence, resulting in a total score of 0.4 points. In summary, there is convincing evidence refuting the relationship between SCN9A and autosomal dominant epilepsy, which significantly outweighs the evidence supporting the relationship. This classification was approved by the ClinGen Epilepsy GCEP on 2/5/21 (SOP Version 8).