Table 3.
Genetic and pathogenetic characteristics of the variants identified in 50 DRVT patients included in this study.
| c.DNA (NM_001165963.4) |
Protein | Inheritance | Nav1.1 Localization |
ACMG Classification |
ClinVar | HGMD | Pathogenicity Classification | |
|---|---|---|---|---|---|---|---|---|
| S_1 | 235A>G | Asp79Gly | de novo | N-ter | LPat | Pat (EIEE) | -; Asp79Asn—NDD/DRVT | Pat |
| S_2 | 241G>A | Asp81Asn | de novo | N-ter | LPat | - | + DRVT | Pat |
| S_3 | 278T>A | Leu93* | de novo | N-ter | Lpat | - | - | Pat |
| S_4 | 298T>A | Phe100Ile | nd | N-ter | LPat | - | -; Phe100.Val—DRVT/EOE/GEFS+ | Pat |
| S_5 | 302G>A | Arg101Gln | de novo | N-ter | LPat | Pat (EIEE) | + DRVT | Pat |
| S_6 | 429_430delGT | Val143Tyrfs*148 | nd | DI-S1 | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_7 | 680T>G | Ile227Ser | de novo | DI-S4 | Pat | Pat (DRVT) | + DRVT | Pat |
| S_8 | 686delT | Val229Alafs*5 | de novo | DI-S4 | LPat | - | - | Pat |
| S_9 | 773T>C | Leu258Pro | nd (ma. -/-) | DI-S5 | LPat | - | - | LPat |
| S_10 | 1025C>T | Ala342Val | de novo | Exter (Loop, IS5-S6) | Pat | Pat (DRVT) | + DRVT | Pat |
| S_11 | 1247A>G | Asn416Ser | de novo | DI-S6 | Pat | LPat (DRVT) | + DRVT | Pat |
| S_12 | 1738C>T | Arg580* | de novo | L1 | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_13 | 1837C>T | Arg613* | de novo | L1 | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_14 | 2134C>T | Arg712* | de novo | L1 | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_51 | 2134C>T | Arg712* | de novo | L1 | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_15 | 2420dupT | Thr808Hisfs*29 | de novo | DII-S1 | Pat | Pat (nd) | - | Pat |
| S_16 | 2585G>A | Arg862Gln | de novo | DII-S4 | Pat | Pat (DRVT/EIEE) | + VUS DRVT/Epi | Pat |
| S_42 | 2692_2706dupGCCATCATCGTCTTC | Ala898_Phe902dup | de novo | DII-S5 | LPat | - | - | Pat |
| S_17 | 2791C>T | Arg931Cys | de novo | Exter (Loop, IIS5-S6) | LPat | Pat (nd) | + DRVT | Pat |
| S_18 | 2837G>A | Arg946His | de novo | Exter (pore-forming) | LPat | Pat (DRVT/EIEE) | + NDD; DRVT, GEFS+ | Pat |
| S_19 | 3225T>A(;)4793A>T | Tyr1075*(;)Tyr1598Phe | de novo; ma. | L2 | LPat; LPat | -; VUS | -; + (Schiz + Aut, GEFS+, DRVT) | Pat/LPat |
| S_21 | 3734_3735ins TGATCAGC | Lys1246Aspfs*27 | pat moz | Exter(Loop) | Pat | - | - | Pat |
| S_22 | 4168G>A | Val1390Met | de novo | Exter (Loop IIIS5-S6) | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
| S_23 | 4274T>A | Leu1425* | de novo | Exter (pore-forming) | LPat | - | - | Pat |
| S_24 | 4388T>C | Phe1463Ser | ma. moz | DIII-S6 | LPat | Pat (DRVT) | + DRVT | Pat |
| S_25 | 4459_4460del | Asn1487Profs*22 | de novo | L3 | LPat | - | - | Pat |
| S_26 | 4532T>G | Met1511Arg | nd | L3 | LPat | LPat (nd) | + DRVT/NDD | Pat |
| S_27 | 4539delA | Lys1513Asnfs*2 | de novo | L3 | LPat | - | - | Pat |
| S_28 | 4547C>A | Ser1516* | de novo | L3 | Pat | Pat (DRVT/EIEE/HM) | + DRVT | Pat |
| S_29 | 4783_4784delCT | Leu1595Thrfs*13 | de novo | Cyto (Loop IV S2-S3) | Pat | Pat/LPat (AD EPI/nd) | - | Pat |
| S_30 | 4787G>A | Arg1596His | pat (epi fam) | Cyto (Loop IV S2-S3) | LPat | ConfIntPat, Pat (DRVT/EIEE) Lpat (-) VUS (-) |
+ GEFS+ (VUS EIEE) | Pat VUS (DRVT) |
| S_31 | 4786C>T | Arg1596Cys | pat (epi fam) | Cyto (Loop IV S2-S3) | Pat | Pat/LPat (FE/GEFS+/EIEE) | + FE/GEFS+/DRVT | Pat VUS (DRVT) |
| S_32 | 4906C>T | Arg1636* | de novo | DIV-S4 | Pat | Pat (DEE6B/DRVT/GEFS+) | + DRVT | Pat |
| S_33 | 4964G>T | Gly1655Val | de novo | Cyto (Loop IV S4-S5) | LPat | - | - p.Gly1655Ala—Epi | Pat |
| S_34 | 5107G>T | Asp1703Tyr | de novo | Exter (Loop IVS5-S6) | LPat | - | + DRVT | Pat |
| S_35 | 5129T>C | Phe1710Ser | de novo | Exter (poreforming) | LPat | - | + VUS DRVT | Pat |
| S_36 | 5178G>A | Trp1726* | de novo | Exter (poreforming) | Lpat | - | + DRVT | Pat |
| S_50 | 5383G>T | Glu1795* | pa moz | C-ter | LPat | Pat (EIEE) | - | Pat |
| S_37 | 5432T>A | Val1811Asp | nd | C-ter | LPat | - | + CAE | LPat |
| S_38 | 5536_5539delAAAC | Lys1846Serfs*11 | de novo | C-ter | Pat | Pat (DEE6B/DRVT/GEFS+) | + DRVT/GEFS+/ASD | Pat |
| S_49 | 5536_5539delAAAC | Lys1846Serfs*11 | de novo | C-ter | Pat | Pat (DEE6B/DRVT/GEFS+) | + DRVT/GEFS+/ASD | Pat |
| S_39 | 5734C>T | Arg1912* | de novo | C-ter | LPat | Pat (HM, AD Epi, EIEE) | + DRVT/GEFS+, FS+ | Pat |
| S_40 | 5779A>G | Arg1927Gly | de novo | C-ter | LPat | - | + ASD/NDD | LPat |
| S_20 | 3421_3429+7del | p.? | nd | LPat | - | - | Pat | |
| S_43 | 2589+2dupT | p.? | de novo | LPat | LPat (DEE6B/DRVT/GEFS+/HM) | + DRVT (c.2589+3A>T) | Pat | |
| S_44 | Ex19_26del | P.? | nd (pa. -/-) | Pat | Pat (DRVT/EIEE) | + del DRVT | Pat | |
| S_45 | 2947-1G>A | p.? | de novo | LPat | Pat (-) | + DRVT | Pat | |
| S_46 | Ex1_26 del | - | de novo | Pat | Pat (DRVT/EIEE) | + del DRVT | Pat | |
| S_47 | 4338+1G>A | p.? | nd | LPat | Pat (EIEE) | + DRVT | Pat | |
| S_48 | Ex1_26del | - | de novo | Pat | Pat (DRVT/EIEE) | + DRVT | Pat |
ma—maternal, pa—paternal, moz—mosaicism, nd—no data, Pat—pathogenic, LPat—likely pathogenic, VUS—variants on unknown significance, confli, EIEE—early infantile epileptic encephalopathy, DRVT—Dravet syndrome, HM—hemiplegic migraine, FS+—febrile seizures plus, GEFS+—generalized epilepsy with febrile seizures plus, ASD—autism spectrum disorder, NDD—neurodevelopmental disorder.