SCN5A Variant I408L

Summary of observed carriers, functional annotations, and structural context for SCN5A I408L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

51%

2/10 effective observations

Estimated BrS1 penetrance

14%

1/10 effective observations

Total carriers

0

0 BrS1 · 0 LQT3 · 0 unaffected

I408L has not been reported in gnomAD. This residue resides in a Non_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 (%)
NA NA NA 0.908 10 69

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
Literature, cohort, and gnomAD – 0 0 0 0 –
Variant features alone – 15 12 2 1 – –

Totals may differ from individual publications due to duplicate patients removed during curation.

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 I408L.
Neighbour residue Distance (Å) Observed variants
403 11
414 10 M414V,
1643 13 I1643L,
404 6 L404V, L404Q,
895 15 L895F,
1773 15
1765 15
249 10 K249X,
247 10 V247L, V247L,
254 8
1771 10 I1771T,
401 10 S401P,
926 11
371 14 Q371E,
250 6
409 5 L409V, L409P,
928 6 L928P,
925 12 I925F,
1650 12 L1650F,
260 13
366 13
934 15
933 11
258 14 V258A,
246 8
935 11 L935P,
1779 14 T1779M
412 7 V412D,
897 15 G897R, G897R, G897E,
924 9 V924I,
927 9 N927S, N927K, N927K,
1466 14 c.4396_4397insG,
245 13 Q245K,
1776 14
369 11 M369K,
1767 14 Y1767C,
244 15
1769 14
402 12 F402L, F402L, F402L,
415 11 A415T,
1649 14 A1649V,
1768 11 I1768V,
1774 15 N1774D, c.5321_5324dupACTT,
256 11
921 14
922 15 V922I,
405 5
248 13
261 14
920 14
930 11 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
255 13
1772 10 L1772V,
251 11
410 6 A410V,
242 13 A242D,
1770 15 I1770V,
929 8
416 14 Y416C,
413 9 A413T, A413E,
408 0
253 7
407 5
936 12
1775 10 F1775V, p.F1775LfsX15,
370 12 T370M,
1642 14 G1642E,
923 12
406 7 N406S, N406K, N406K,
252 12
411 6 V411M,
243 12
932 7
1647 14
257 9
400 11 G400R, G400R, G400E, G400A,
931 11
1646 11