Submission Details

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from early infantile epileptic encephalopathy, 12 to developmental epileptic encephalopathy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. **

Pathogenic variants in the PLCB1 gene have been reported in the literature in several individuals with developmental and epileptic encephalopathy, usually characterized by refractory infantile onset seizures, EEG abnormalities- often with hypsarrhythmia, neurologic and developmental regression and long term cognitive and motor impairment. Homozygous or compound heterozygous loss of function variants have been primarily reported in association with this phenotype supporting an autosomal recessive inheritance pattern. Sequence variants (PMIDs: 24684524, 30554916, 31054490, 31883110) as well as large multi-exon deletions (PMID:26818157, 31883110) have been reported in the literature, often from individuals with consanguineous family history. Of note, a recurrent deletion which encompasses the promoter and exons 1-3 of the gene has been reported in multiple individuals (approximate reported breakpoints GRCh37 20:803442-8099252 to 8520654-8575520) (PMIDs:20833646, 22690784, 24684524). Evidence supporting this gene disease pair includes experimental data as well. Supporting experimental data has been reported in a knockout mouse model (PMID:9305844) that exhibited no phenotype in the heterozygous state, but demonstrated delayed growth, low viability and recurrent tonic-clonic seizures in the homozygous state. In summary PLCB1 is definitively associated with autosomal recessive developmental and epileptic encephalopathy. This has been demonstrated in both the clinical and research settings and this evidence has been maintained over time.