SCN5A Variant E346K
Summary of observed carriers, functional annotations, and structural context for SCN5A E346K. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT3 penetrance
1%
0/24 effective observations
Estimated BrS1 penetrance
10%
2/24 effective observations
Total carriers
14
0 BrS1 · 0 LQT3 · 14 unaffected
Variant features alone are equivalent to phenotyping 2 individuals for Brugada syndrome and 0 individuals for LQT3.
In silico predictors
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density BrS (%) | Penetrance Density LQT3 (%) |
|---|---|---|---|---|---|
| -0.06 | 0.064 | 0.09 | 0.337 | 32 | 2 |
PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).
Reported carrier data
| Source | Year | Carriers | Unaffected | LQT3 | BrS1 | Other | Other Disease |
|---|---|---|---|---|---|---|---|
| 28837624 | 2017 | 1 | 0 | 0 | 1 | AF | |
| Literature, cohort, and gnomAD | – | 14 | 14 | 0 | 0 | – | |
| Variant features alone | – | 15 | 13 | 0 | 2 | – | – |
Totals may differ from individual publications due to duplicate patients removed during curation.
Functional data
Peak and late/persistent current values are relative to wild-type (100% indicates no change). V1/2 activation and inactivation denote the membrane potentials (mV) at which half-maximal current is achieved.
| PubMed ID | Year | Cell Type | Peak Current (% WT) | V1/2 Activation (mV) | V1/2 Inactivation (mV) | Late/Persistent Current (% WT) |
|---|---|---|---|---|---|---|
| 28837624 | 2017 |
Nearby variants
Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.
| Neighbour residue | Distance (Å) | Observed variants |
|---|---|---|
| 277 | 7 | |
| 276 | 11 | L276P, L276Q, |
| 348 | 8 | P348A |
| 317 | 11 | K317N, K317E, K317M, |
| 360 | 12 | |
| 279 | 9 | |
| 355 | 14 | F355C, F355I, |
| 278 | 12 | H278D, H278R, |
| 356 | 11 | D356N, |
| 318 | 15 | |
| 904 | 13 | W904X, |
| 343 | 11 | |
| 871 | 15 | |
| 354 | 10 | |
| 349 | 10 | D349N, |
| 1550 | 12 | |
| 357 | 14 | |
| 274 | 11 | G274C, |
| 273 | 15 | |
| 319 | 13 | G319R, G319C, G319S, |
| 325 | 12 | L325R, |
| 324 | 14 | |
| 321 | 8 | S321Y, |
| 872 | 14 | D872N, |
| 345 | 4 | |
| 275 | 14 | N275K, |
| 280 | 14 | C280Y, |
| 912 | 15 | Q912R, |
| 323 | 10 | |
| 347 | 5 | |
| 351 | 6 | G351S, G351D, G351V, G351C, |
| 320 | 10 | T320N, |
| 350 | 10 | H350Q, |
| 342 | 13 | |
| 1551 | 14 | D1551Y, D1551N, |
| 346 | 0 | E346X, E346D, E346G, E346K, |
| 344 | 7 | A344S, |
| 322 | 9 | |
| 352 | 9 | Y352C, |
| 380 | 14 | |
| 908 | 13 | |
| 281 | 13 | V281M, |
| 353 | 10 | T353I, |