Submission Details

SCN3A was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2017 (Lamar et al., PMID: 28235671). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism (gain-of-function) AND/OR inheritance pattern (autosomal dominant) AND/OR phenotypic variability (with or without malformations of cortical development) but also there is a report of loss-of-function associated variant as well. Therefore, the following disease entities have been lumped into one disease entity, developmental and epileptic encephalopathy (OMIM: 617938). 16 variants (variant types of missense, in-frame indel, and frameshift) that have been reported in 29 probands in 7 publications (PMIDs: 28235671, 27848944, 29466837, 29740860, 31618753, 31677917, 32515017) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain-of-function. This gene-disease association is also supported by Voltage-Clamp Electrophysiology study (PMIDs: 32515017, 29466837). Authors generated disease-associated Nav1.3 variants and expressed these variants in a heterologous mammalian cell line(HEK-293T) for characterization via whole-cell voltage clamp recording. As a result, prominent gain of channel function with an increase in the slowly-inactivating current component and/or a left/hyperpolarizing shift in the voltage dependence of channel activation was shown in the cell expressed variant alleles. In summary, SCN3A is definitively associated with autosomal dominant developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.