SCN5A Variant L466F

Summary of observed carriers, functional annotations, and structural context for SCN5A L466F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

3%

0/17 effective observations

Estimated BrS1 penetrance

13%

2/17 effective observations

Total carriers

7

1 BrS1 · 0 LQT3 · 6 unaffected

L466F is present in 6 alleles in gnomAD. This residue resides in a Non_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 (%)
-3.32 0.998 -0.14 0.768 9 6

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
24721456 2014 1 0 1 0
Literature, cohort, and gnomAD – 7 6 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)
24721456 2014

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 L466F.
Neighbour residue Distance (Å) Observed variants
451 15
452 14 G452D,
453 14 V453M,
454 13
455 13
456 12 V456M,
457 11
458 11 p.R458VfsX12, R458C, R458H,
459 10 S459G,
460 9
461 8 L461V,
462 8 E462K, E462A,
463 7 M463T, M463R,
464 5
465 4 p.P465LfsX5,
466 0 L466F, L466F,
467 4
468 5 P468L,
469 7 V469I,
470 8 N470K, N470K,
471 8
472 9
473 10 E473X,
474 11 R474G, R474K,
475 11 R475K, R475S, R475S,
476 12
477 13 c.1428_1431delCAAG,
478 13
479 14
480 14 K480N, K480N,
481 15 R481W, R481Q