SCN5A Variant V1405L

Summary of observed carriers, functional annotations, and structural context for SCN5A V1405L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

2%

0/12 effective observations

Estimated BrS1 penetrance

66%

7/12 effective observations

Total carriers

2

2 BrS1 · 0 LQT3 · 0 unaffected

V1405L 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 5 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 (%)
-2.92 1 1.16 0.937 94 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
12106943 2002 1 0 1 0
19843921 2009 1 0 1 0
21273195 2011 2 0 2 0
20129283 2010 2 0 2 0
Literature, cohort, and gnomAD – 2 0 0 2 –
Variant features alone – 15 10 0 5 – –

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)
32533946 2020 HEK 14 -2.6 -1.6
12106943 2002
19843921 2009
21273195 2011
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 V1405L.
Neighbour residue Distance (Å) Observed variants
1355 13
1403 9
1357 10 A1357V,
733 13 F733L, F733L, F733L,
741 14 p.M741_T742delinsI ,
745 15
1352 9
1406 4 G1406R, G1406R, G1406E,
1453 14
1351 11 M1351R, M1351V,
739 12
1449 14 Y1449S, Y1449C,
812 13 L812Q,
1350 7 I1350L, I1350T,
1344 14 F1344L, F1344L, F1344S, F1344L,
731 11 T731I,
1411 10
1353 7 V1353M,
1407 6
737 9
1410 9
1358 13 G1358W, G1358R, G1358R,
1348 11 F1348L, F1348L, F1348L,
1404 4
1349 6
749 14
1346 7 L1346I, L1346P,
1359 15 K1359N, K1359M, K1359N,
1341 15
1356 12 c.4066_4068delTT,
1412 10 L1412F,
1408 6 G1408R, G1408R,
735 6 A735V, A735E, A735T,
732 11
1360 14 F1360C,
734 10 M734V, c.2201dupT,
1401 10
1354 11
738 9
1405 0 V1405M, V1405L, V1405L,
740 14 p.N740del,
1409 7 Y1409C, Y1409X,
815 14
1400 13 V1400I,
1343 12
1345 11 W1345C, W1345C,
1342 10
736 8 L736P,
730 15 N730K, N730K,
1749 14 I1749N,
1347 11
1415 15
1414 14 Q1414H, Q1414H,
1402 8
1413 12