SCN5A Variant H445D

Summary of observed carriers, functional annotations, and structural context for SCN5A H445D. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

0%

0/25 effective observations

Estimated BrS1 penetrance

9%

2/25 effective observations

Total carriers

15

1 BrS1 · 0 LQT3 · 14 unaffected

H445D is present in 14 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 (%)
-1.37 0.011 -1.22 0.63 12 4

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
18378609 2008 2 0 0 2 AF
22818067 2012 3 0 0 3 AF
25650408 2015 1 0 1 0
28086167 2017 1 0 0 1 MI
Literature, cohort, and gnomAD – 15 14 0 1 –
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)
18378609 2008
22818067 2012
25650408 2015
28086167 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 H445D.
Neighbour residue Distance (Å) Observed variants
430 15 K430E,
431 14
432 14
433 13 R433S, R433C, R433H,
434 13
435 12
436 11
437 11 A437V,
438 10 M438L, M438L, M438T,
439 9 E439K, E439V,
440 8
441 8 L441F,
442 7
443 5
444 4 E444fsX14,
445 0 H445D, H445Y, H445Q, H445Q,
446 4 E446K,
447 5 c.1338+2T>A, c.1339-24G>A, A447S, A447G,
448 7
449 8 T449A, Y449C,
450 8
451 9
452 10 G452D,
453 11 V453M,
454 11
455 12
456 13 V456M,
457 13
458 14 p.R458VfsX12, R458C, R458H,
459 14 S459G
460 15