Table 2.
Overview of Pathogenic and Likely Pathogenic Variants in SADS Cohort
| Case | Age at Death (yrs) | Sex | Circumstances of Death |
Symptoms Before Death | Gene | Chr | Start | Ref | Alt | cDNA change | Amino Acid Change∗ | ACMG Classification† | ACMG Criteria† |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| P1 | 31 | M | NA | NA | KCNH2 | 7 | 150671971 | G | C | c.C135G | p.N45K | LP | PM1,PM2,PM5,PP3 |
| P2 | 22 | M | Rest | None | KCNH2 | 7 | 150655191 | A | G | c.T872C | p.M291T | LP | PS4,PM2 |
| P3 | 19 | F | Sleep | None | KCNH2 | 7 | 150649550 | G | A | c.C1520T | p.P507L | P | PM1,PM2,PM5,PP3 |
| P4 | 44 | F | Rest | None | KCNH2 | 7 | 150649880 | C | T | c.G1190A | p.R397H | LP | PS3,PM5,PP3 |
| P5 | 22 | F | Sleep | None | KCNH2 | 7 | 150647481 | G | A | c.C2173T | p.Q725X | P | PVS1,PM2,PP3 |
| P6 | 22 | F | NA | NA | KCNH2 | 7 | 150644460 | GC | G | c.3107_3108C | p.G1036AfsX21 | P | PVS1,PM2,PP1,PP3 |
| P7 | 39 | F | Sleep | Seizures | KCNH2 | 7 | 150648593 | C | T | c.G1888A | p.V630I | P | PS4,PM1,PM5,PP3,PP5 |
| P8 | 10 | M | Light activity | Seizures | KCNQ1 | 11 | 2466615 | C | G | c.C287G | p.T96R | LP | PS3,PM2 |
| P9 | 57 | M | Sleep | None | KCNQ1 | 11 | 2610045 | C | T | c.C1354T | p.R452W | LP | PS4,PM5,PP3 |
| P10 | 42 | F | Sleep | None | KCNQ1 | 11 | 2797262 | C | T | c.C1663T | p.R555C | P | PS3,PS4,PP3 |
| P11 | 4 | F | Light activity | NA | KCNQ1 | 11 | 2604712 | G | A | c.G969A (homozygous) | p.W323X (homozygous) | P | PVS1,PM2,PM3,PP3 |
| P12 | 1 | M | Sleep | None | CACNA1C | 12 | 2789725 | G | GC | c.5608_5608delinsGC | p.Q1872PfsX24 | LP | PVS1,PM2 |
| P13 | 20 | M | Sleep | None | RYR2 | 1 | 237586538 | G | A | c.G995A | p.R332Q | P | PS4,PM1,PM2,PM5,PP3 |
| P14 | 18 | M | Extreme emotion | Syncope | RYR2 | 1 | 237608789 | G | A | c.G1259A | p.R420Q | P | PS4,PS3,PM1,PM2,PM5,PP3 |
| P15 | 17 | M | Exercise | None | RYR2 | 1 | 237617856 | A | C | c.A1458C | p.Q486H | LP | PM2,PP3,PP4‡ |
| P16 | 15 | M | Exercise | Seizures | RYR2 | 1 | 237754262 | C | T | c.C4130T | p.A1377V | LP | PM2,PP3,PP4‡ |
| P17 | 12 | M | Exercise | None | RYR2 | 1 | 237777676 | G | A | c.G5248A | p.G1750R | LP | PM2,PP3,PP4‡ |
| P18 | 8 | M | Exercise | None | RYR2 | 1 | 237794789 | A | G | c.A6503G | p.H2168R | LP | PM2,PM5,PP3,PP4 |
| P19 | 12 | F | Light activity | Syncope | RYR2 | 1 | 237801693 | T | G | c.T6829G | p.C2277G | LP | PM1,PM2,PM5,PP3 |
| P20 | 6 | M | Exercise | Syncope | RYR2 | 1 | 237804283 | G | A | c.G7202A | p.R2401H | P | PS4,PM1,PM2,PM5,PP3 |
| P21 | 11 | M | Extreme emotion | None | RYR2 | 1 | 237870332 | G | A | c.G9664A | p.A3222T | LP | PM2,PM6,PP2,PP3 |
| P22 | 22 | F | Extreme emotion | NA | RYR2 | 1 | 237538090 | C | T | c.C458T | p.T153I | P | PS4,PM1,PP3‡ |
| P23 | 24 | M | Rest | None | RYR2 | 1 | 237538090 | C | T | c.C458T | p.T153I | P | PS4,PM1,PP3‡ |
| P24 | 18 | M | Rest | None | RYR2 | 1 | 237886554 | C | G | c.C10681G | p.L3561V | LP | PM1,PM2,PP3‡ |
| P25 | 8 | M | Extreme emotion | Seizures | RYR2 | 1 | 237942026 | G | A | c.G11836A | p.G3946S | P | PS4,PM1,PM2,PM5,PP3 |
| P26 | 3 | F | Rest | NA | RYR2 | 1 | 237947016 | A | G | c.A12004G | p.M4002V | P | PS2,PM1,PM2,PM5,PP3 |
| P27 | 13 | M | Sleep | Seizures | RYR2 | 1 | 237947164 | C | T | c.C12152T | p.A4051V | LP | PM1,PM2,PP3 |
| P28 | 6 | M | Light activity | Syncope | RYR2 | 1 | 237957170 | C | T | c.C13786T | p.P4596S | P | PM1,PM2,PP1,PP3,PP4 |
| P29 | 41 | M | Light activity | Chest pain | RYR2 | 1 | 237957207 | G | A | c.G13823A | p.R4608Q | P | PS4,PM1,PM2,PM5,PP1,PP3 |
| P30 | 2 | M | Sleep | None | SCN5A | 3 | 38627337 | G | A | c.C2632T | p.R878C | P | PS4,PS3,PM2,PM5,PP3 |
| P31 | 1 | M | Sleep | None | SCN5A | 3 | 38620964 | C | T | c.G3248A | p.G1083D | LP | PS4,PM2 |
| P32 | 39 | M | NA | None | SCN5A | 3 | 38671833 | G | A | c.C361T | p.R121W | P | PS3,PS4,PM2,PP1,PP3 |
| P33 | 24 | F | Light activity | None | SCN5A | 3 | 38655264 | G | A | c.C673T | p.R225W | P | PS3,PS4 |
| P34 | 21 | F | NA | NA | SCN1B | 19 | 35524731 | G | A | c.G536A | p.W179X | P | PVS1,PS1,PS4,PS3 |
| P35 | 55 | F | Rest | None | TTN | 2 | 179391915 | C | A | c.G80605T | p.G26869X | LP | PVS1,PM2 |
| P36 | 33 | F | NA | Seizures | TTN | 2 | 179640969 | C | T | c.G5484A | p.W1828X | LP | PVS1, PS4‡ |
| P37 | NA | F | NA | NA | TTN | 2 | 179640969 | C | T | c.G5484A | p.W1828X | LP | PVS1, PS4‡ |
| P38 | 32 | M | Rest | None | PLN | 6 | 118880200 | T | G | c.T116G | p.L39X | P | PVS1,PS4,PP5 |
| P39 | 22 | M | Exercise | None | PKP2 | 12 | 32975414 | CT | C | c.1825_1826G | p.R609GfsX3 | LP | PVS1,PM2 |
| P40 | 54 | M | Sleep | Palpitations | MYH7 | 14 | 23886806 | C | T | c.G4259A | p.R1420Q | LP | PS4,PM2,PM5,PP3 |
Alt = alternate allele; cDNA = coding DNA; Chr = chromosome; LP = likely pathogenic; NA = not available; P = pathogenic; Ref = reference allele; other abbreviations as in Table 1.
∗
The following transcripts were used: CACNA1C:NM_001167625; KCNH2:NM_000238; KCNQ1:NM_000218; PKP2:NM_001005242; PLN:NM_002667; RYR2:NM_001035; SCN1B:NM_199037; SCN5A:NM_000335; TTN:NM_003319.
†
See ACMG guidelines (12) for further information on classification criteria.
‡
For these variants, 1 criterion was moved to a higher weight using consensus and professional judgment of 3 observers, in line with the ACMG guidelines.