SCN5A Variant G1408R

Summary of observed carriers, functional annotations, and structural context for SCN5A G1408R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

1/38 effective observations

Estimated BrS1 penetrance

33%

12/38 effective observations

Total carriers

28

8 BrS1 · 1 LQT3 · 19 unaffected

G1408R has not been reported 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 (%)
-7.79 1 -4.96 0.98 56 3

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
14523039 2003 13 0 0 3 SSS
16643399 2006 1 0 1 0
20031634 2009 13 0 4 0
20541041 2010 1 1 0 0
26921764 2016 1 0 1 0
26941339 2016 1 0 1 0
28341781 2017 1 0 1 0
19251209 2009 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 2 0 2 0
29574140 2018 1 0 1 0
30059973 2018 2 2 0 0
Literature, cohort, and gnomAD – 28 19 1 8 –
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)
20384651 2010 0
14523039 2003 HEK-tSA201 0
16643399 2006
20031634 2009
20541041 2010
26921764 2016
26941339 2016
28341781 2017
20539757 2010
19251209 2009
20129284 2010
20129285 2010
20188230 2010
20129283 2010
20129283 2010
20129283 2010
29574140 2018
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 G1408R.
Neighbour residue Distance (Å) Observed variants
1355 12
1403 8
1357 10 A1357V,
1417 13
1352 8
1406 5 G1406R, G1406R, G1406E,
1457 14
1453 11
1351 11 M1351V, M1351R,
739 13
1397 13 c.4189delT, c.4190delA,
1449 11 Y1449S, Y1449C,
1350 9 I1350L, I1350T,
1723 13 T1723N,
1344 14 F1344L, F1344S, F1344L, F1344L,
1450 12
1398 12 V1398M,
1411 5
1353 8 V1353M,
1407 3
737 12
1410 5
1714 13 D1714G,
1358 12 G1358R, G1358R, G1358W,
1348 10 F1348L, F1348L, F1348L,
1404 6
1423 15 D1423H,
1721 14
1349 6
1753 14 T1753A
1346 9 L1346I, L1346P,
1359 13 K1359M, K1359N, K1359N,
1341 14
1356 9 c.4066_4068delTT,
1412 5 L1412F,
1408 0 G1408R, G1408R,
735 11 A735T, A735E, A735V,
1420 13 G1420R, G1420D, G1420V, G1420P,
1360 11 F1360C,
734 14 M734V, c.2201dupT,
1401 6
1425 14
1399 12
1454 15
1354 12
1427 13 A1427S, A1427E,
1424 10 I1424V,
738 12
1405 6 V1405M, V1405L, V1405L,
1409 6 Y1409C, Y1409X,
1400 8 V1400I,
1421 14
1718 15 S1718R, S1718R, S1718R,
1343 14
1345 10 W1345C, W1345C,
1717 14 L1717P,
1342 12
1416 12 c.4245+1G>A, c.4245+1G>C, c.4245+2T>A, A1416E, A1416G,
736 13 L736P,
1749 12 I1749N,
1347 12
1415 10
1428 13 A1428S, A1428V,
1414 9 Q1414H, Q1414H,
1402 5
1413 8