SCN5A Variant N1325S

Summary of observed carriers, functional annotations, and structural context for SCN5A N1325S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

92%

25/33 effective observations

Estimated BrS1 penetrance

4%

1/33 effective observations

Total carriers

23

0 BrS1 · 23 LQT3 · 0 unaffected

N1325S 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 (%)
-4.21 0.947 -0.41 0.923 18 72

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
8541846 1995 4 4 0 0
10973849 2000 1 1 0 0
15840476 2005 2 2 0 0
17905336 2007 1 1 0 0
17118339 2007 4 4 0 0
24342415 2014 1 1 0 0
25904541 2015 1 1 0 0
27566755 2016 21 21 0 0
19716085 2009 3 3 0 0
30059973 2018 4 4 0 0
Literature, cohort, and gnomAD – 23 0 23 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)
14736542 2004 mouse 108 238
8541846 1995
10973849 2000
14736536 2004
15840476 2005
17490620 2007
17905336 2007
19762097 2011
29017927 2017
17118339 2007
17157817 2007
21677263 2011
24342415 2014
25904541 2015
27566755 2016
8917568 1996 Oocytes 1.7 2.1 3000
19716085 2009
30059973 2018
32533946 2020 HEK 114 -9.6 -3.2

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 N1325S.
Neighbour residue Distance (Å) Observed variants
1328 6 V1328M,
1659 13
1271 11 W1271C, W1271C,
1480 10 c.4437+5G>A, c.4438-1C>T,
1472 10 p.N1472del, N1472S,
1315 9
1314 12 c.3940_3941delCT,
1320 9 M1320I, M1320I, M1320I,
1333 14
1656 13
1270 13 A1270S,
1477 11 K1477N, K1477N,
1471 14
1762 14 p.I1762del, I1762M,
1470 15
1478 13 K1478E,
1313 14
1660 13 I1660V, I1660S,
1329 7 G1329S,
1769 14
1316 13 R1316Q, R1316L,
1766 11 M1766L, M1766V, M1766L, M1766T,
1319 10 G1319V,
1479 8
1473 9 F1473S, F1473C,
1334 14 I1334V,
1468 15 V1468F, V1468A,
1663 13
1474 13
1324 4
1481 14 G1481R, G1481R, G1481E, G1481V,
1317 13 F1317C,
1327 7
1318 12
1330 9 A1330T, A1330P, A1330D,
1321 8 R1321K,
1323 6 V1323G,
1770 14 I1770V
1482 15
1322 6 c.3963+2T>C, c.3963+4A>G,
1312 11
1326 5 A1326S,
1763 14 V1763M, V1763L, V1763L,
1311 13 L1311P,
1332 12 P1332Q, P1332L,
1476 6 Q1476X, Q1476R,
1331 11 I1331V,
1475 11 p.Q1475NfsX6, Q1475L,
1469 12 I1469V,
1269 14 N1269S,
1325 0 N1325S,