Table 4.
SCN8A-related epilepsies identified in clinical patients through WES and/or NGS.
| Variant | Location | Mutation | Alteration on biophysical properties or/and Clinical report | Reference |
|---|---|---|---|---|
| Inherited mutation | ||||
| K101R | N-terminus | Missense | NR | (Butler et al., 2017b) |
| I137M | D1 (S1) | Missense | NR | (Johannesen et al., 2019) |
| T164M | DI (S2) | Missense | NR | (Butler et al., 2017a) |
| G269R | DI (S5) | Missense | Non-functional channel | (Wengert et al., 2019) |
| R530W | DI (S6)-DII (S1) | Missense | NR | (Olson et al., 2015) |
| N544 fs*39 | DI (S6)-DII (S1) | Frameshift | NR | (Johannesen et al., 2019) |
| S702T | DI (S6)-DII (S1) | Missense | NR | (Jang et al., 2019) |
| G822R | DII (S3) | Missense | Non-functional channel | (Wengert et al., 2019) |
| V891M | DII (S5) | Missense | NR | (Johannesen et al., 2019) |
| L1290V | DIII (S3-S4) | Missense | NR | (Carvill et al., 2013) |
| L1331V | DIII (S5) | Missense | NR | (Larsen et al., 2015) |
| T1360N | DIII (S5-S6) | Missense | Shift steady-state inactivation to more negative values | (Wengert et al., 2019) |
| E1442K | DIII (S5-S6) | Missense | NR | (Liu et al., 2018) |
| I1464T | DIII (S6)-DIV (S1) | Missense | NR | (Johannesen et al., 2019) |
| G1476D | DIII (S6)-DIV (S1) | Missense | NR | (Han et al., 2017) |
| E1483K | DIII (S6)-DIV (S1) | Missense | NR | (Gardella et al., 2016) |
| I1583T | DIV (S3) | Missense | NR | (Berghuis et al., 2015) |
| V1598A | DIV (S3) | Missense | NR | (Wang et al., 2017a) |
| R1638C | DIV (S4) | Missense | Shift steady-state activation to more positive values | (Wengert et al., 2019) |
| V1758A | DIV (S6) | Missense | Shift steady-state activation to more positive values | (Zaman et al., 2019) |
| N1877S | C-Terminus | Missense | NR | (Butler et al., 2017b; Johannesen et al., 2019) |
| R1904C | C-Terminus | Missense | NR | (Schreiber et al., 2020) |
| De novo mutation | ||||
| Exons 2-14 | – | Deletion | NR | (Berghuis et al., 2015) |
| c.-8A > G UTR | 5′ UTR | Eight base pairs change upstream of start codon | NR | (Johannesen et al., 2019) |
| c.4296A>G | DIII | Splice-site mutation | NR | (Denis et al., 2019) |
| M139I | D1 (S1) | Missense | Shift steady-state inactivation to more negative values Enhanced persistent current Slightly impaired fast channel inactivation |
(Zaman et al., 2019) |
| I142V | D1 (S1) | Missense | NR | (Denis et al., 2019; Kim et al., 2019) |
| A205E | D1 (S1) | Missense | NR | (Lindy et al., 2018) |
| F210L | D1 (S1) | Missense | NR | (Mercimek-Mahmutoglu et al., 2015) |
| V211L | DI (S3) | Missense | NR | (Denis et al., 2019) |
| V211A | DI (S3) | Missense | NR | (Berkovic et al., 2018) |
| L213P | D1 (S3) | Missense | NR | (Denis et al., 2019) |
| G214D | DI (S3-S4) |
Missense | NR | (Allen et al., 2013) |
| N215R | DI (S3-S4) |
Missense | NR | (Larsen et al., 2015) |
| N215D | DI (S3-S4) |
Missense | NR | (Deciphering Developmental Disorders Study, 2015) |
| V216D | DI (S3-S4) |
Missense | NR | (Ohba et al., 2014) |
| R223G | D1 (S4) | Missense | Reduced current density Increased current amplitude provokes by ramp voltage protocol |
(de Kovel et al., 2014; Berkovic et al., 2018; Denis et al., 2019) |
| I231T | D1 (S4) | Missense | NR | (Berkovic et al., 2018) |
| S232P | D1 (S4) | Missense | NR | (Wang et al., 2017a) |
| T239S | D1 (S4-S5) | Missense | NR | (Møller et al., 2016) |
| I240V | DI (S4-S5) | Missense | NR | (McNally et al., 2016) |
| L257V | DI (S5) | Missense | NR | (Schreiber et al., 2020) |
| F260S | DI (S5) | Missense | NR | (Larsen et al., 2015; Boerma et al., 2016) |
| C261F | DI (S5) | Missense | NR | (Rim et al., 2018; Kim et al., 2019) |
| L267S | DI (S5) | Missense | NR | (Malcolmson et al., 2016) |
| G317A | DI (S5-S6) | Missense | NR | (Denis et al., 2019) |
| F360A | DI (S5-S6) | Missense | NR | (Rolvien et al., 2017) |
| M367V | DI (S5-S6) | Missense | NR | (Lindy et al., 2018) |
| N374K | DI (S5-S6) | Missense | Shift steady-state activation to more negative values | (Johannesen et al., 2019; Zaman et al., 2019) |
| T386R | DI (S5-S6) | Missense | NR | (Lindy et al., 2018) |
| Y401H | DI (S6) | Missense | NR | (Gardella et al., 2018) |
| L405M | DI (S6) | Missense | NR | (Denis et al., 2019) |
| L407F | DI (S6) | Missense | NR | (Fung et al., 2015; Zhang et al., 2015) |
| A408T | DI (S6) | Missense | NR | (Trump et al., 2016; Denis et al., 2019) |
| V410L | DI (S6) | Missense | NR | (Larsen et al., 2015) |
| L483F | DI (S6) –DII (S1) | Missense | Slight shift steady-state activation to more negative values | (Zaman et al., 2019) |
| E587Ter | DI (S6)-DII (S1) | Nonsense | NR | (Schreiber et al., 2020) |
| I763V | DII (S1) | Missense | NR | (Butler et al., 2017b; Hewson et al., 2018; Lindy et al., 2018; Costain et al., 2019; Johannesen et al., 2019) |
| T767I | DII (S1) | Missense | Decreased current density Increased current amplitude provokes by voltage ramp protocol |
(Estacion et al., 2014; Gardella et al., 2018; Lindy et al., 2018) |
| V791F | DII (S2) | Missense | NR | (Xie et al., 2019) |
| V842E | DII (S4) | Missense | NR | (Lindy et al., 2018) |
| S845F | DII (S4) | Missense | NR | (Lindy et al., 2018) |
| F846S | DII (S4) | Missense | NR | (Ohba et al., 2014) |
| L848W | DII (S4) | Missense | NR | (Denis et al., 2019) |
| R850Q | DII (S4) | Missense | Shift steady state inactivation to more negative values Increased persistent current Impaired inactivation |
(Fung et al., 2015; Zhang et al., 2015; Lindy et al., 2018; Kim et al., 2019; Tsang et al., 2019; Pan and Cummins, 2020; Schreiber et al., 2020) |
| R850E | DII (S4) | Missense | NR | (Wang et al., 2017a) |
| R850L | DII (S4) | Missense | NR | (Gardella et al., 2018) |
| L864V | DII (S4-S5) | Missense | NR | (Gardella et al., 2018) |
| L875Q | DII (S5) | Missense | NR | (Allen et al., 2013) |
| A890T | DII (S5) | Missense | NR | (Fung et al., 2015; Larsen et al., 2015; Zhang et al., 2015) |
| V891M | DII (S5) | Missense | NR | (Wang et al., 2017a) |
| V960D | DII (S6) | Missense | NR | (Larsen et al., 2015) |
| L971V | DII (S6) | Missense | NR | (Kim et al., 2019) |
| S978R | DII (S6)-DIII (S1) | Missense | NR | (Kim et al., 2019) |
| S978G | DII (S6)-DIII (S1) | Missense | NR | (Parrini et al., 2017; Gardella et al., 2018) |
| N984K | DII (S6)-DIII (S1) | Missense | Shift steady-state activation to more negative values | (Blanchard et al., 2015; Boerma et al., 2016) |
| G1050S | DII (S6)-DIII (S1) | Missense | NR | (McMichael et al., 2015) |
| S1073N | DII (S6)-DIII (S1) | Missense | NR | (Lindy et al., 2018) |
| E1201K | DIII (S1) | Missense | NR | (Johannesen et al., 2019) |
| V1274M | DIII (S3) | Missense | NR | (Jang et al., 2019) |
| V1315M | DIII (S4-S5) | Missense | NR | (Trump et al., 2016; Bagnasco et al., 2018; Denis et al., 2019) |
| N1318S | DIII (S4-S5) |
Missense | NR | (Johannesen et al., 2019; Lin et al., 2019) |
| A1319S | DIII (S4-S5) |
Missense | NR | (Lindy et al., 2018) |
| A1319D | DIII (S4-S5) |
Missense | NR | (Johannesen et al., 2019) |
| A1323S | DIII (S4-S5) |
Missense | NR | (Trump et al., 2016) |
| A1323T | DIII (S4-S5) |
Missense | NR | (Johannesen et al., 2019) |
| I1327V | DIII (S4-S5) |
Missense | NR | (Vaher et al., 2013; Singh et al., 2015; Trump et al., 2016) |
| N1329D | DIII (S4-S5) | Missense | NR | (Butler et al., 2017b) |
| V1330M | DIII (S4-S5) | Missense | NR | (Schreiber et al., 2020) |
| L1332R | DIII (S5) | Missense | NR | (Butler et al., 2017b) |
| P1428_K1473del | DIII (S5-S6) | Missense | NR | (Larsen et al., 2015) |
| G1451S | DIII (S6) | Missense | Non-functional channel | (Blanchard et al., 2015; Denis et al., 2019) |
| N1466K | DIII (S6)-DIV (S1) | Missense | NR | (Ohba et al., 2014) |
| N1466T | DIII (S6)-DIV (S1) | Missense | NR | (Ohba et al., 2014) |
| Q1470K | DIII (S6)-DIV (S1) | Missense | NR | (Pons et al., 2018; Denis et al., 2019) |
| G1475R | DIII (S6)-DIV (S1) | Missense | Enhanced persistent current | (Hussain et al., 2016; Ortiz Madinaveitia et al., 2017; Parrini et al., 2017; Wang et al., 2017a; Gardella et al., 2018; Lindy et al., 2018; Xiao et al., 2018; Kim et al., 2019; Trivisano et al., 2019; Zaman et al., 2019; Ranza et al., 2020; Schreiber et al., 2020) |
| G1476S | DIII (S6)-DIV (S1) | Missense | NR | (Lindy et al., 2018) |
| I1479V | DIII (S6)-DIV (S1) | Missense | NR | (Larsen et al., 2015; Lindy et al., 2018; Schreiber et al., 2020) |
| E1483K | DIII (S6)-DIV (S1) | Missense | NR | (Johannesen et al., 2019) |
| A1491V | DIII (S6)-DIV (S1) | Missense | Shift steady-state activation to more negative values Increased current amplitude provokes by slow voltage ramp protocol |
(Gardella et al., 2018; Lindy et al., 2018; Zaman et al., 2019) |
| M1494T | DIII (S6)-DIV (S1) | Missense | NR | (Kim et al., 2019) |
| K1498M | DIII (S6)-DIV (S1) | Missense | NR | (Gardella et al., 2018) |
| M1529V | DIV (S1) | Missense | NR | (Johannesen et al., 2019) |
| I1532F | DIV (S1) | Missense | NR | (Møller et al., 2016; Gardella et al., 2018) |
| M1536I | DIV (S1) | Missense | NR | (Lindy et al., 2018) |
| F1547V | DIV (S1-S2) |
Missense | NR | (Gardella et al., 2018) |
| F1588L | DIV (S3) | Missense | NR | (Johannesen et al., 2019) |
| V1592L | DIV (S3) | Missense | NR | (Larsen et al., 2015; Ranza et al., 2020) |
| S1596C | DIV (S3) | Missense | NR | (Fung et al., 2015; Zhang et al., 2015; Boerma et al., 2016) |
| I1605R | DIV (S3-S4) |
Missense | NR | (Larsen et al., 2015) |
| T1614A | DIV (S3-S4) |
Missense | NR | (Johannesen et al., 2019) |
| R1617Q | DIV (S4) | Missense | Increased persistent current Increased peak current density Shift steady state activation to more negative values Shift steady-state inactivation to more positive values |
(Rauch et al., 2012; Ohba et al., 2014; Dyment et al., 2015; Fung et al., 2015; Larsen et al., 2015; Zhang et al., 2015; Fung et al., 2017; Lindy et al., 2018; Johannesen et al., 2019; Schreiber et al., 2020) |
| R1620L | DIV (S4) | Missense | NR | (Rossi et al., 2017) |
| L1621W | DIV (S4) | Missense | NR | (Fung et al., 2015) |
| G1625R | DIV (S4) | Missense | NR | (Deciphering Developmental Disorders Study, 2015) |
| L1630P | DIV (S4) | Missense | NR | (Schreiber et al., 2020) |
| I1631N | DIV (S4) | Missense | NR | (Lindy et al., 2018) |
| M1645I | DIV (S4-S5) |
Missense | NR | (Zhang et al., 2015) |
| A1650T | DIV (S4-S5) |
Missense | NR | (Ohba et al., 2014; Larsen et al., 2015; Parrini et al., 2017; Gardella et al., 2018; Trivisano et al., 2019) |
| A1650V | DIV (S4-S5) |
Missense | NR | (Lindy et al., 2018; Johannesen et al., 2019) |
| F1754S | DIV (S6) | Missense | NR | (Trump et al., 2016) |
| V1758A | DIV (S6) | Missense | Shift steady-state activation to more positive values | (Balciuniene et al., 2019; Johannesen et al., 2019; Zaman et al., 2019) |
| N1759T | DIV (S6) | Missense | NR | (Kim et al., 2019) |
| A1763G | DIV (S6) | Missense | NR | (Denis et al., 2019) |
| I1764M | DIV (S6) | Missense | NR | (Gardella et al., 2018) |
| N1768D | C-Terminus | Missense | Increased spontaneous firing Paroxysmal depolarizing-shift-like complexes, Increased firing frequency Increased persistent current |
(Veeramah et al., 2012) |
| V1771I | C-Terminus | Missense | NR | (Johannesen et al., 2019) |
| Q1801E | C-Terminus | Missense | NR | (Larsen et al., 2015) |
| R1820X | C-Terminus | Nonsense | NR | (Møller et al., 2016; Johannesen et al., 2019) |
| R1831Q | C-Terminus | Missense | NR | (Liu et al., 2018) |
| R1831W | C-Terminus | Missense | NR | (Jang et al., 2019) |
| T1852I | C-Terminus | Missense | NR | (Lindy et al., 2018; Heyne et al., 2019) |
| L1865P | C-Terminus | Missense | NR | (Trump et al., 2016) |
| R1866Q | C-Terminus | Missense | NR | (Kothur et al., 2018; Johannesen et al., 2019) |
| E1870D | C-Terminus | Missense | NR | (Boerma et al., 2016) |
| R1872L | C-Terminus | Missense | Enhanced persistent current Increased peak current density Shift steady-state activation to more negative values Shift steady-state inactivation to more positive values |
(Wagnon et al., 2016; Sprissler et al., 2017; Lindy et al., 2018; Zaman et al., 2019; Schreiber et al., 2020) |
| R1872Q | C-Terminus | Missense | Enhanced persistent current Increase peak current density Shift steady-state activation to more negative values Shift steady-state inactivation to more positive values |
(Larsen et al., 2015; Horvath et al., 2016; Hussain et al., 2016; Arafat et al., 2017; Atanasoska et al., 2018; Lindy et al., 2018) |
| R1872W | C-Terminus | Missense | Enhanced persistent current Increased peak current density Shift steady-state activation to more negative values Shift steady-state inactivation to more positive values |
(Ohba et al., 2014; Larsen et al., 2015; Takahashi et al., 2015; Gardella et al., 2018; Denis et al., 2019; Kim et al., 2019; Zaman et al., 2019) |
| N1877S | C-Terminus | Missense | NR | (Anand et al., 2016; Parrini et al., 2017; Wang et al., 2017a; Lindy et al., 2018; Costain et al., 2019; Epifanio et al., 2019; Jain et al., 2019; Ranza et al., 2020) |
| P1878S | C-Terminus | Missense | NR | (Lindy et al., 2018) |
| Non genetic origin mutations reported* | ||||
| R45Q | N-terminus | Missense | NR | (Encinas et al., 2019; Heyne et al., 2019) |
| A108fsXTer7 | N-terminus | Truncated gene | NR | (Encinas et al., 2019) |
| T166I | DI (S2) | Missense | NR | (Encinas et al., 2019) |
| I202N | DI (S3) | Missense | NR | (Butler et al., 2017a) |
| V211L | DI (S3) | Missense | NR | (Encinas et al., 2019) |
| V211A | DI (S3) | Missense | NR | (Encinas et al., 2019) |
| R220H | D1 (S4) | Missense | NR | (Oates et al., 2018) |
| R223S | DI (S4) | Missense | NR | (Encinas et al., 2019) |
| T239A | DI (S4-S5) | Missense | NR | (Encinas et al., 2019) |
| I240V | DI (S4-S5) | Missense | NR | (Encinas et al., 2019) |
| I240L | DI (S4-S5) | Missense | NR | (Encinas et al., 2019) |
| L257V | DI (S5) | Missense | NR | (Encinas et al., 2019) |
| L267V | DI (S5) | Missense | NR | (Denis et al., 2019) |
| I268L | DI (S5) | Missense | NR | (Encinas et al., 2019) |
| F360A | DI (S5-S6) | Missense | NR | (Encinas et al., 2019) |
| M367V | DI (S5-S6) | Missense | NR | (Encinas et al., 2019) |
| R381Q | DI (S5-S6) | Missense | NR | (Encinas et al., 2019) |
| T386R | DI (S5-S6) | Missense | NR | (Encinas et al., 2019; Schreiber et al., 2020) |
| S399P | DI (S6) | Missense | NR | (Encinas et al., 2019; Heyne et al., 2019) |
| V410L | DI (S6) | Missense | NR | (Encinas et al., 2019) |
| Y414F | DI (S6)-DII (S1) | Missense | NR | (Butler et al., 2017a) |
| E416K | DI (S6)-DII (S1) | Missense | NR | (Encinas et al., 2019) |
| Q417P | DI (S6)-DII (S1) | Missense | NR | (Encinas et al., 2019) |
| R530Q | DI (S6)-DII (S1) | Missense | NR | (Encinas et al., 2019) |
| E587Ter | DI (S6)-DII (S1) | Nonsense | NR | (Encinas et al., 2019) |
| R598W | DI (S6)-DII (S1) | Missense | NR | (Encinas et al., 2019) |
| G692R | DI (S6)-DII (S1) | Missense | NR | (Encinas et al., 2019) |
| I763V | DII (S1) | Missense | NR | (Butler et al., 2017a; Encinas et al., 2019) |
| T767I | DII (S1) | Missense | Shift steady-state activation to more negative values | (Estacion et al., 2014) |
| L840P | DII (S3-S4) | Missense | NR | (Encinas et al., 2019) |
| L840F | DII (S3-S4) | Missense | NR | (Encinas et al., 2019) |
| S845F | DII (S4) | Missense | NR | (Encinas et al., 2019) |
| L864V | DII (S4-S5) | Missense | NR | (Trivisano et al., 2019) |
| l868T | DII (S4-S5) | Missense | NR | (Encinas et al., 2019) |
| A874T | DII (S4-S5) | Missense | NR | (Encinas et al., 2019) |
| V881A | DII (S5) | Missense | NR | (Encinas et al., 2019) |
| E936K | DII (S6) | Missense | NR | (Johannesen et al., 2019) |
| L969M | DII (S6) | Missense | NR | (Encinas et al., 2019) |
| S979F | DII (S6)-DIII (S1) | Missense | NR | (Encinas et al., 2019) |
| G1050S | DII (S6)-DIII (S1) | Missense | NR | (Encinas et al., 2019) |
| Y1241C | DIII (S2) | Missense | NR | (Encinas et al., 2019; Johannesen et al., 2019) |
| S1308P | DIII (S4) | Missense | NR | (Encinas et al., 2019) |
| V1315M | DIII (S4-S5) |
Missense | NR | (Encinas et al., 2019) |
| L1320F | DIII (S4-S5) | Missense | NR | (Encinas et al., 2019; Schreiber et al., 2020) |
| A1323P | DIII (S4-S5) |
Missense | NR | (Encinas et al., 2019) |
| I1327V | DIII (S4-S5) |
Missense | NR | (Oates et al., 2018) |
| M1328T | DIII (S4-S5) |
Missense | NR | (Encinas et al., 2019) |
| N1329D | DIII (S4-S5) |
Missense | NR | (Butler et al., 2017a) |
| G1451S | DIII (S6) | Missense | NR | (Encinas et al., 2019) |
| G1461V | DIII (S6) | Missense | NR | (Encinas et al., 2019; Schreiber et al., 2020) |
| N1466K | DIII (S6)-DIV (S1) | Missense | NR | (Encinas et al., 2019) |
| F1467C | DIII (S6)-DIV (S1) | Missense | NR | (Encinas et al., 2019) |
| Q1470H | DIII (S6)-DIV (S1) | Missense | NR | (Trivisano et al., 2019) |
| I1479V | DIII (S6)-DIV (S1) | Missense | NR | (Encinas et al., 2019) |
| A1491V | DIII (S6)-DIV (S1) | Missense | Shift steady-state activation to more negative values | (Johannesen et al., 2018; Trivisano et al., 2019) |
| M1492V | DIII (S6)-DIV (S1) | Missense | NR | (Encinas et al., 2019; Ranza et al., 2020) |
| Q1501K | DIII (S6)-DIV (S1) | Missense | NR | (Encinas et al., 2019) |
|
Splice donor
c.4419+1A>G |
DIII (S6)-DIV (S1) | Truncated gene | NR | (Encinas et al., 2019) |
| M1536I | DIV (S1) | Missense | NR | (Encinas et al., 2019) |
| V1592L | DIV (S3) | Missense | NR | (Encinas et al., 2019) |
| I1594L | DIV (S3) | Missense | NR | (Encinas et al., 2019) |
| S1596C | DIV (S3) | Missense | NR | (Encinas et al., 2019) |
| T1614A | DIV (S3-S4) |
Missense | NR | (Encinas et al., 2019) |
| R1617Q | DIV (S4) | Missense | Enhanced persistent current Increased peak current density Shift steady-state activation to more negative values Shift steady-state inactivation to more positive values |
(Encinas et al., 2019) |
| R1617P | DIV (S4) | Missense | NR | (Encinas et al., 2019) |
| G1625R | DIV (S4) | Missense | NR | (Encinas et al., 2019) |
| L1630P | DIV (S4) | Missense | NR | (Encinas et al., 2019) |
| F1642C | DIV (S4-S5) |
Missense | NR | (Encinas et al., 2019) |
| A1650T | DIV (S4-S5) |
Missense | NR | (Trivisano et al., 2019) |
| A1650V | DIV (S4-S5) |
Missense | NR | (Encinas et al., 2019) |
| I1654N | DIV (S4-S5) |
Missense | NR | (Johannesen et al., 2019) |
| N1759S | DIV (S6) | Missense | NR | (Encinas et al., 2019; Schreiber et al., 2020) |
| M1760I | DIV (S6) | Missense | Shift steady-state activation to more negative values Increase action potential firing frequency |
(Liu et al., 2019) |
| N1768D | C-Terminus | Missense | Increased spontaneous firingParoxysmal depolarizing shift like complexes Increased firing frequency Enhanced persistent current |
(Veeramah et al., 2012; Encinas et al., 2019) |
| K1807N | C-Terminus | Missense | NR | (Encinas et al., 2019) |
| R1831W | C-Terminus | Missense | NR | (Encinas et al., 2019) |
| D1833H | C-Terminus | Missense | NR | (Johannesen et al., 2019) |
| T1852I | C-Terminus | Missense | NR | (Encinas et al., 2019; Ranza et al., 2020) |
| R1872L | C-Terminus | Missense | Increased persistent current Increased peak current density Shift steady state activation to more negative values Shift steady inactivation to more positive values |
(Encinas et al., 2019) |
| N1877S | C-Terminus | Missense | NR | (Johannesen et al., 2019; Schreiber et al., 2020) |
| R1904C | C-Terminus | Missense | NR | (Encinas et al., 2019) |
*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. Not Reported (NR); Domain (D); Segment (S).