SCN5A Variant E462A

Summary of observed carriers, functional annotations, and structural context for SCN5A E462A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

40%

2/11 effective observations

Estimated BrS1 penetrance

9%

0/11 effective observations

Total carriers

1

0 BrS1 · 1 LQT3 · 0 unaffected

E462A has not been reported 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 1 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.27 0.779 -0.57 0.771 0 35

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
19716085 2009 1 1 0 0
Literature, cohort, and gnomAD – 1 0 1 0 –
Variant features alone – 15 14 1 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). 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)
25904541 2015 HEK 91 -3 1 95
19716085 2009

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 E462A.
Neighbour residue Distance (Å) Observed variants
447 15 c.1338+2T>A, c.1339-24G>A, A447S, A447G,
448 14
449 14 T449A, Y449C,
450 13
451 13
452 12 G452D,
453 11 V453M,
454 11
455 10
456 9 V456M,
457 8
458 8 p.R458VfsX12, R458C, R458H,
459 7 S459G,
460 5
461 4 L461V,
462 0 E462K, E462A,
463 4 M463T, M463R,
464 5
465 7 p.P465LfsX5,
466 8 L466F, L466F,
467 8
468 9 P468L,
469 10 V469I,
470 11 N470K, N470K,
471 11
472 12
473 13 E473X,
474 13 R474G, R474K,
475 14 R475K, R475S, R475S,
476 14
477 15 c.1428_1431delCAAG