SCN5A Variant N406K

Summary of observed carriers, functional annotations, and structural context for SCN5A N406K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

69%

6/15 effective observations

Estimated BrS1 penetrance

15%

2/15 effective observations

Total carriers

5

0 BrS1 · 5 LQT3 · 0 unaffected

N406K has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 2 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 (%)
-5.89 1 -5.43 0.832 20 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
24112685 2014 1 1 0 0
29983085 2018 1 1 0 0
15840476 2005 1 1 0 0
19996378 2010 1 1 0 0
20541041 2010 1 1 0 0
22360817 2012 2 2 0 0
23631430 2013 1 1 0 0
27566755 2016 1 1 0 0
19716085 2009 1 1 0 0
30059973 2018 2 2 0 0
Literature, cohort, and gnomAD – 5 0 5 0 –
Variant features alone – 15 12 1 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)
24112685 2014 CHO 21 8.6 2.9 550
29983085 2018 HEK 31 -3 -3
16885209 2006 HEK 40
15840476 2005
19996378 2010
20541041 2010
22360817 2012
23631430 2013
24117196 2014
25254341 2014
27566755 2016
19716085 2009
30059973 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 N406K.
Neighbour residue Distance (Å) Observed variants
403 7
414 13 M414V,
939 14 L939F,
404 7 L404V, L404Q,
1773 11
1765 9
396 14 V396L, V396A,
1653 11
254 14
1771 6 I1771T,
401 7 S401P,
1652 14 M1652T, M1652R,
1764 10 c.5290delG, V1764F,
371 11 Q371E,
250 12
409 5 L409V, L409P,
928 10 L928P,
1650 10 L1650F,
260 14
366 14
1656 14
933 14
246 14
935 10 L935P,
412 10 V412D,
924 14 V924I,
1762 15 p.I1762del, I1762M,
1470 11
927 12 N927S, N927K, N927K,
1466 10 c.4396_4397insG,
1776 13
369 10 M369K,
1767 8 Y1767C,
1660 13 I1660V, I1660S,
1654 13
1769 8
402 7 F402L, F402L, F402L,
1766 12 M1766L, M1766V, M1766L, M1766T,
415 15 A415T,
1649 12 A1649V,
1768 5 I1768V,
1774 12 N1774D, c.5321_5324dupACTT,
1473 14 F1473S, F1473C,
256 13
399 12
397 12 I397V, I397F, I397T,
405 4
1657 11
1709 14 p.T1709del, T1709R, T1709M,
930 15 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1772 7 L1772V,
410 7 A410V,
1770 9 I1770V,
929 13
413 11 A413T, A413E,
408 7
253 12
407 6
936 13
1763 13 V1763M, V1763L, V1763L,
1760 14
1467 13
1775 10 F1775V, p.F1775LfsX15
370 12 T370M,
923 15
1469 13 I1469V,
406 0 N406S, N406K, N406K,
368 15
411 10 V411M,
932 9
398 11
1647 14
257 12
400 9 G400R, G400R, G400E, G400A,
931 13
1646 12
1463 13 N1463Y,