SCN5A Variant V411M

Summary of observed carriers, functional annotations, and structural context for SCN5A V411M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

83%

19/28 effective observations

Estimated BrS1 penetrance

5%

1/28 effective observations

Total carriers

18

0 BrS1 · 17 LQT3 · 1 unaffected

V411M 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 1 individuals for Brugada syndrome and 2 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.94 1 -1.73 0.947 13 63

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
21193062 2011 1 1 0 0
10961955 2000 1 1 0 0
15840476 2005 1 1 0 0
16712702 2006 1 1 0 0
20541041 2010 1 1 0 0
22360817 2012 1 1 0 0
22885918 2012 1 1 0 0
23098067 2012 4 4 0 0
23631430 2013 1 1 0 0
24606995 2014 1 1 0 0
26496715 2016 2 2 0 0
26498160 2016 1 0 0 1 SD
26669661 2016 6 5 0 0
26940925 2016 1 1 0 0
27485560 2016 1 1 0 0
22721569 2012 1 1 0 0
27566755 2016 7 7 0 0
19716085 2009 3 3 0 0
30059973 2018 10 10 0 0
Literature, cohort, and gnomAD – 18 1 17 0 –
Variant features alone – 15 12 2 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)
21193062 2011 HEK 100 -8.1 -7.9 176
10961955 2000
15840476 2005
16712702 2006
20541041 2010
22360817 2012
22885918 2012
23098067 2012
23631430 2013
24606995 2014
26496715 2016
26498160 2016
26669661 2016
26940925 2016
27485560 2016
29017927 2017
22721569 2012
26888838 2015
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 V411M.
Neighbour residue Distance (Å) Observed variants
403 14
414 5 M414V,
939 13 L939F,
1643 12 I1643L,
404 11 L404V, L404Q,
937 15
1778 12
1773 13
249 6 K249X,
247 9 V247L, V247L,
254 11
1771 11 I1771T,
1777 13 V1777M, V1777L, V1777L,
418 10 E418K,
926 14
250 6
409 7 L409V, L409P,
928 10 L928P,
925 14 I925F,
1650 13 L1650F,
417 11
933 10
246 6
935 12 L935P,
1779 10 T1779M,
412 4 V412D,
924 13 V924I,
1470 15
927 14 N927S, N927K, N927K,
245 9 Q245K,
1776 10
244 12
1769 14
415 6 A415T,
1649 13 A1649V,
1768 13 I1768V,
1774 13 N1774D, c.5321_5324dupACTT,
256 13
405 11
248 11
241 13
420 14
419 13 Q419X,
930 13 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
255 14
1772 9 L1772V,
1645 12 T1645M,
239 14 I239V, I239V ,
251 10
410 4 A410V,
1780 13 E1780G
242 10 A242D,
929 9
416 11 Y416C,
413 6 A413T, A413E,
408 6
253 8
407 6
936 11
1775 7 F1775V, p.F1775LfsX15,
1642 11 G1642E,
406 10 N406S, N406K, N406K,
252 11
411 0 V411M,
243 11
932 9
1647 13
257 13
931 14
1646 9
1782 14