Table 3.

SCN3A-related epilepsies identified in clinical patients through WES and/or NGS.

Variant	Location	Mutation	Disease	Alteration on biophysical properties or/and Clinical report	Reference
Inherited mutation
K354Q	DI	Missense	CCE	Enhanced persistent current and current amplitude provokes by ramp protocol	(Holland et al., 2008; Estacion et al., 2010)
R357Q	DI (S5-S6)	Missense	Focal epilepsy	Reduced current density Enhanced current amplitude provokes by ramp voltage protocol	(Vanoye et al., 2014)
R621C	DI-DII	Missense	BECTS FS	Centro-temporal spikes (EEG)	(Zaman et al., 2018)
E1111K	DII-III	Missense	Focal epilepsy	Enhanced current amplitude provokes by ramp voltage protocol Enhanced persistent current	(Vanoye et al., 2014)
M1323V	DIII (S5-S6)	Missense	Focal epilepsy	Enhanced current amplitude provokes by ramp voltage protocol	(Vanoye et al., 2014)
C121Wβ1 β1 subunit mutation*	Extracellular Ig loop	Substitution * Chinese hamster ovary (CHO) cells co-expressing human Nav1.3 sodium channels and C121Wβ1	GEFS+	Resistant to enter into close-state inactivation Shift steady state inacativation to more positive values	(Lucas et al., 2005)
Chromosome 2q24.3 Involves the SCN1A,SCN2A, and SCN3A genes	Chromosome	Duplication (1.57 Mb)	BFNS	NR	(Heron et al., 2010)
Chromosome 2q24.3 Involves the SCN1A,SCN2A, and SCN3A genes	Chromosome	Duplication (2.0 Mb)	Neonatal- infantile epilepsy	Facial flushing, head turning to the left, eye deviation, bilateral arm jerking movement	(Raymond et al., 2011)
Chromosome 2q23.3q24.3 Involves the SCN2A and SCN3A genes	Chromosome	Mosaic duplication (12 Mb)	DS BFNIS	Focal seizures with secondary generalization Atonic seizures (EEG)	(Vecchi et al., 2011)
De novo mutation
L247P	DI	Missense	Childhood focal epilepsy	Reduced current density associated with low protein expression	(Lamar et al., 2017)
I875T	DII (S4-S5)	Missense	EE	Enhanced persistente current Shift steady-state activation and inactivation to more negative values Generalized convulsion, infantile spasm	(Miyatake et al., 2018; Smith et al., 2018; Zaman et al., 2018)
P1333L	DIII	Missense	EIEE	Enhanced persistent current Increased current density Shift steady-state activation and inactivation to more negative values	(Trujillano et al., 2017; Zaman et al., 2018)
M1765I	DIV	Missense	Refractory epilepsy	Focal and generalized seizures Myoclonus and epileptic spasms	(Inuzuka et al., 2019)
V1769A	DIV (S6)	Missense	EIEE	Enhanced persistent current Shift steady-state activation to more negative values Shift steady-state inactivation to more positive values	(Zaman et al., 2018)
chromosome 2q24.3 Involves the SCN1A,SCN2A, and SCN3A genes	chromosome	Deletion (1.1 Mb)	WS	Typical hypsarrhythmic pattern (sleeping and awake)	(Chong et al., 2018)
Non genetic origin mutations reported*
N302S	DI	Missense	GEFS+	Shift steady-state activation and inactivation to more positive values Slower recovery from inactivation with 500 ms duration pre pulse Faster recovery from inactivation with 20 ms duration pre pulse	(Chen et al., 2015)
D766N	DII (S2)	Missense	Focal epilepsy	Increased current amplitude by ramp voltage protocol	(Vanoye et al., 2014)

*Non genetic origin mutations reported: Mutations described through clinical diagnosis, but the mutation type (Mendelian or de novo) were not reported, mainly due to the lack of parents to perform genotyping and difficulty in contacting the family. Cryptogenic childhood epilepsy (CCE); Benign epilepsy with centro-temporal spikes (BECTS); Generalized epilepsy with febrile seizures plus (GEFS+); West syndrome (WS); Febrile seizures (FS); Benign familial neonatal-infantile seizures (BFNIS); Benign familial neonatal seizures (BFNS); Dravet syndrome (DS); Epileptic encephalopathy (EE); Early infantile epileptic encephalopathy (EIEE); Not Reported (NR); Domain (D); Segment (S); Electroencephalography (EEG).