SCN5A Variant M438L

Summary of observed carriers, functional annotations, and structural context for SCN5A M438L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

2%

0/11 effective observations

Estimated BrS1 penetrance

32%

3/11 effective observations

Total carriers

1

1 BrS1 · 0 LQT3 · 0 unaffected

M438L has not been reported in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 2 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 (%)
0.45 0 1.5 0.311 42 0

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
29709101 2018 1 0 1 0
Literature, cohort, and gnomAD – 1 0 0 1 –
Variant features alone – 15 13 0 2 – –

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)
29709101 2018

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 M438L.
Neighbour residue Distance (Å) Observed variants
423 15
424 14 I424M,
425 14 A425P, A425T,
426 13
427 13
428 12 E428K,
429 11 p.E429del, E429K,
430 11 K430E,
431 10
432 9
433 8 R433H, R433S, R433C,
434 8
435 7
436 5
437 4 A437V,
438 0 M438T, M438L, M438L,
439 4 E439V, E439K,
440 5
441 7 L441F,
442 8
443 8
444 9 E444fsX14,
445 10 H445Q, H445Q, H445Y, H445D,
446 11 E446K,
447 11 c.1339-24G>A, A447S, A447G, c.1338+2T>A,
448 12
449 13 T449A, Y449C,
450 13
451 14
452 14 G452D,
453 15 V453M,