SCN5A Variant P468L

Summary of observed carriers, functional annotations, and structural context for SCN5A P468L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

3%

0/17 effective observations

Estimated BrS1 penetrance

10%

1/17 effective observations

Total carriers

7

1 BrS1 · 0 LQT3 · 6 unaffected

P468L is present in 3 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 0 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 (%)
-2.24 0.001 0.2 0.205 10 3

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
19829766 2009 4 0 1 0
Literature, cohort, and gnomAD – 7 6 0 1 –
Variant features alone – 15 15 0 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)
19829766 2009 HEK 107 -1.4 2.8

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 P468L.
Neighbour residue Distance (Å) Observed variants
453 15 V453M,
454 14
455 14
456 13 V456M,
457 13
458 12 p.R458VfsX12, R458C, R458H,
459 11 S459G,
460 11
461 10 L461V,
462 9 E462K, E462A,
463 8 M463T, M463R,
464 8
465 7 p.P465LfsX5,
466 5 L466F, L466F,
467 4
468 0 P468L,
469 4 V469I,
470 5 N470K, N470K,
471 7
472 8
473 8 E473X,
474 9 R474G, R474K,
475 10 R475K, R475S, R475S,
476 11
477 11 c.1428_1431delCAAG,
478 12
479 13
480 13 K480N, K480N,
481 14 R481W, R481Q,
482 14 M482I, M482I, M482I
483 15