SCN5A Variant R526H

Summary of observed carriers, functional annotations, and structural context for SCN5A R526H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

1%

0/30 effective observations

Estimated BrS1 penetrance

25%

7/30 effective observations

Total carriers

20

6 BrS1 · 0 LQT3 · 14 unaffected

R526H 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 (%)
-0.94 0 2.91 0.476 14 1

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
24795344 2014 2 0 2 0
19412328 2008 1 0 0 1 DCM
23321620 2013 1 0 1 0
27554632 2017 4 0 1 3 CM
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
Literature, cohort, and gnomAD 20 14 0 6
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)
27554632 2017
24795344 2014 HEK 75
19412328 2008
23321620 2013
24573164 2014 HEK 88 -1.81
20129283 2010
20129283 2010

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 R526H.
Neighbour residue Distance (Å) Observed variants
511 15
512 14 T512I,
513 14 R513H, R513C, R513P, c.1537delC,
514 13 G514C,
515 13
516 12
517 11 R517S, R517S,
518 11
519 10 S519F,
520 9 M520V, M520R,
521 8 K521E, c.1562delA,
522 8 P522S,
523 7 R523S, R523C, R523H,
524 5 S524Y, c.1570_1571insG
525 4 S525G,
526 0 R526H, R526C,
527 4 G527R, G527R,
528 5 S528R, S528R, S528R,
529 7
530 8 F530V, F530S,
531 8 T531I, T531A,
532 9 F532C, F532L, F532L, F532L,
533 10 R533H, R533S, R533C,
534 11
535 11 R535X, R535Q, R535G,
536 12 D536H,
537 13
538 13 G538D,
539 14
540 14
541 15