SCN5A Variant E428K

Summary of observed carriers, functional annotations, and structural context for SCN5A E428K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

11%

2/29 effective observations

Estimated BrS1 penetrance

1/29 effective observations

Total carriers

1 BrS1 · 2 LQT3 · 16 unaffected

E428K is present in 14 alleles in gnomAD. This residue resides in a Non_Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 0 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 (%)
-3.14	0.041	2.02	0.664	10	14

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
15996170	2005	1		0	0	0
18378609	2008	1		0	0	1	AF
19026623	2009	1		1	0	0
22818067	2012	3		0	0	2	AF
23631430	2013	1		1	0	0
28341781	2017	1		0	1	0
Literature, cohort, and gnomAD	–	19	16	2	1		–
Variant features alone	–	15	15	0	0	–	–

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). V_1/2 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)	V_1/2 Activation (mV)	V_1/2 Inactivation (mV)	Late/Persistent Current (% WT)
29449639	2018	CHO	151	0	0	100
15996170	2005
18378609	2008
19026623	2009
22818067	2012
23631430	2013
28341781	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.

Previously observed variants near E428K.
Neighbour residue	Distance (Å)	Observed variants
413	15	A413T, A413E,
414	14	M414V,
415	14	A415T,
416	13	Y416C,
417	13
418	12	E418K,
419	11	Q419X,
420	11
421	10
422	9
423	8
424	8	I424M,
425	7	A425T, A425P,
426	5
427	4
428	0	E428K,
429	4	E429K, p.E429del,
430	5	K430E,
431	7
432	8
433	8	R433S, R433C, R433H,
434	9
435	10
436	11
437	11	A437V,
438	12	M438L, M438L, M438T,
439	13	E439K, E439V,
440	13
441	14	L441F
442	14
443	15