SCN5A Variant E446K

Summary of observed carriers, functional annotations, and structural context for SCN5A E446K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

0%

0/164 effective observations

Estimated BrS1 penetrance

1%

1/164 effective observations

Total carriers

154

0 BrS1 · 0 LQT3 · 154 unaffected

E446K is present in 154 alleles in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 1 individuals for Brugada syndrome and 0 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.63 0.959 0.18 0.732 15 8

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

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT3 BrS1 Other Other Disease
22338672 2012 1 0 0 1 Post MI TdP
21596231 2011 1 0 0 1 DCM
29325976 2018 1 0 1 0
Literature, cohort, and gnomAD – 154 154 0 0 –
Variant features alone – 15 14 0 1 – –

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.

Published electrophysiology measurements.
PubMed ID Year Cell Type Peak Current (% WT) V1/2 Activation (mV) V1/2 Inactivation (mV) Late/Persistent Current (% WT)
22338672 2012 tsA201 70 -1 -6.16 133
21596231 2011
25102755 2014
29325976 2018

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.

Previously observed variants near E446K.
Neighbour residue Distance (Å) Observed variants
431 15
432 14
433 14 R433S, R433C, R433H,
434 13
435 13
436 12
437 11 A437V,
438 11 M438L, M438L, M438T,
439 10 E439K, E439V,
440 9
441 8 L441F,
442 8
443 7
444 5 E444fsX14,
445 4 H445D, H445Y, H445Q, H445Q,
446 0 E446K,
447 4 c.1338+2T>A, c.1339-24G>A, A447S, A447G,
448 5
449 7 T449A, Y449C,
450 8
451 8
452 9 G452D,
453 10 V453M,
454 11
455 11
456 12 V456M,
457 13
458 13 p.R458VfsX12, R458C, R458H,
459 14 S459G,
460 14
461 15 L461V