SCN5A Variant E1225K

Summary of observed carriers, functional annotations, and structural context for SCN5A E1225K. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

7%

1/24 effective observations

Estimated BrS1 penetrance

66%

15/24 effective observations

Total carriers

14

11 BrS1 · 1 LQT3 · 2 unaffected

E1225K is present in 1 alleles 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 4 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 (%)
-3.91 1 -2.67 0.95 72 8

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
14961552 2003 3 0 2 0
15840476 2005 1 1 0 0
17404158 2007 1 0 1 0
22840528 2012 2 0 2 0
23321620 2013 1 0 1 0
24721456 2014 1 0 1 0
26921764 2016 1 0 1 0
26941339 2016 1 0 1 0
28341781 2017 2 0 2 0
28781330 2017 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
29574140 2018 2 0 2 0
30059973 2018 3 3 0 0
Literature, cohort, and gnomAD – 14 2 1 11 –
Variant features alone – 15 11 0 4 – –

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)
12106943 2002
14961552 2003
15840476 2005
17404158 2007
22840528 2012
23321620 2013
24721456 2014
26921764 2016
26941339 2016
28341781 2017
28781330 2017
20129283 2010
20129283 2010
20129283 2010
20129283 2010
29574140 2018
30059973 2018
32533946 2020 HEK 36 3.9 11.5

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 E1225K.
Neighbour residue Distance (Å) Observed variants
1233 12 K1233E,
1218 11 S1218T, S1218I,
1304 10 T1304M,
1217 14
1243 11 D1243N,
1234 11
1698 14 A1698T
1285 15
1299 13 c.3894delC,
1220 10 G1220E,
1673 8
1675 12
1681 13 c.5040_5042delTTAinsC, Y1681F,
1694 14
1241 14
1226 4
1695 12 Q1695X,
1669 12
1221 7 A1221V,
1242 11
1676 8 M1676T, M1676I, M1676I, M1676I,
1219 10 S1219N,
1672 11 S1672Y,
1699 15
1239 6 L1239P,
1306 12 R1306S, R1306H,
1305 14
1680 12 A1680T, A1680P,
1246 14
1235 7
1302 13 p.L1302Vfs18,
1231 12 E1231K,
1237 11 V1237F,
1307 13
1228 9 Y1228H, Y1228C, Y1228F,
1678 13 N1678S,
1223 7 c.3667delG,
1697 10
1222 6 p.L1222LfsX7, L1222R,
1230 10 E1230K,
1227 8
1300 13
1674 13 F1674V,
1229 6
1301 9
1696 10
1700 13
1677 9
1224 7
1670 14
1240 9 E1240Q,
1225 0 E1225K, G1225K,
1232 15 R1232W, R1232Q,
1238 11
1679 14
1236 8 K1236R, K1236N, K1236N,
1303 8 R1303W, R1303Q,