This variant, previously titled GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7, has been reclassified based on the report by Fasham et al. (2020), which noted that the K655R variant has a high frequency (0.2%) and is present in homozygous state in the gnomAD database, inconsistent with it being causative of a monogenic seizure disorder.
In a patient with a phenotype consistent with GEFS+, Singh et al. (2009) identified a heterozygous 1964A-G transition in the SCN9A gene, resulting in a lys655-to-arg (K655R) substitution in a highly conserved residue in the large intracellular loop between domains I and II. The mutation was not identified in 562 control chromosomes. The patient had febrile seizures, idiopathic generalized epilepsy, and generalized spike-wave patterns on EEG. Singh et al. (2009) found this mutation in 2 patients diagnosed with Dravet syndrome (607208), one of whom also had a mutation in the SCN1A gene (182389). Singh et al. (2009) suggested that SCN9A mutations may have a modifier effect in partner with SCN1A mutations.
In 2 sisters from a nonconsanguineous Brazilian family with GEFS+, Alves et al. (2019) identified the K655R mutation in the SCN9A gene. The mutation, which was found by whole-exome sequencing, was also present in their unaffected father.
