SCN5A Variant R535Q

Summary of observed carriers, functional annotations, and structural context for SCN5A R535Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

38%

4/18 effective observations

Estimated BrS1 penetrance

6%

0/18 effective observations

Total carriers

8

0 BrS1 · 3 LQT3 · 5 unaffected

R535Q is present in 5 alleles in gnomAD. This residue resides in a Non_Hotspot region for Brugada syndrome and a 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 (%)
-2.04 0.997 0.83 0.655 1 50

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
24349418 2013 1 1 0 0
19716085 2009 2 2 0 0
Literature, cohort, and gnomAD – 8 5 3 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)
24349418 2013 hiPSC-CM 59
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 R535Q.
Neighbour residue Distance (Å) Observed variants
520 15 M520V, M520R,
521 14 K521E, c.1562delA,
522 14 P522S,
523 13 R523S, R523C, R523H,
524 13 c.1570_1571insG, S524Y,
525 12 S525G,
526 11 R526C, R526H,
527 11 G527R, G527R,
528 10 S528R, S528R, S528R,
529 9
530 8 F530V, F530S,
531 8 T531A, T531I,
532 7 F532L, F532C, F532L, F532L,
533 5 R533S, R533C, R533H,
534 4
535 0 R535G, R535X, R535Q,
536 4 D536H,
537 5
538 7 G538D,
539 8
540 8
541 9
542 10
543 11 F543L, F543L, F543L
544 11
545 12
546 13
547 13
548 14
549 14
550 15