SCN5A Variant Y1449S

Summary of observed carriers, functional annotations, and structural context for SCN5A Y1449S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

4%

0/11 effective observations

Estimated BrS1 penetrance

53%

5/11 effective observations

Total carriers

1

1 BrS1 · 0 LQT3 · 0 unaffected

Y1449S 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 (%)
-8.59 0.977 -5.9 0.967 68 1

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
24775617 2013 1 0 1 0
Literature, cohort, and gnomAD – 1 0 0 1 –
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)
24775617 2013

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 Y1449S.
Neighbour residue Distance (Å) Observed variants
888 14
1355 8
1357 12 A1357V,
1430 14 D1430N,
808 15 R808C, R808H, R808P,
1352 7
1445 11 Y1445H,
1457 12
1453 7
1455 11
1447 9
1444 12 L1444I,
1351 6 M1351V, M1351R,
1449 0 Y1449S, Y1449C,
1452 6
812 12 L812Q,
1350 11 I1350L, I1350T,
1429 11
1344 13 F1344L, F1344S, F1344L, F1344L,
806 13 V806M,
1450 4
1411 11
1451 7 V1451L, V1451D,
1353 11 V1353M,
1407 15
1458 13 S1458Y,
1348 6 F1348L, F1348L, F1348L,
1349 9
1431 13 S1431C,
1422 14 M1422R,
1346 13 L1346I, L1346P,
1418 14
805 14 S805L,
892 13 F892I,
1359 12 K1359M, K1359N, K1359N,
1356 8 c.4066_4068delTT,
1412 9 L1412F,
810 14
1408 11 G1408R, G1408R,
889 13
1456 11
1360 13 F1360C,
1459 14 c.4376_4379delTCTT
1401 14
1425 9
1454 9
1354 11
1427 13 A1427S, A1427E,
1446 7
1424 11 I1424V,
1448 6 I1448L, I1448T,
1405 14 V1405M, V1405L, V1405L,
809 11
1409 14 Y1409C, Y1409X,
1400 15 V1400I,
1421 12
885 15
1345 12 W1345C, W1345C,
1443 12 N1443S,
1416 12 c.4245+1G>A, c.4245+1G>C, c.4245+2T>A, A1416E, A1416G,
1347 11
1415 10
1428 9 A1428S, A1428V,
1414 14 Q1414H, Q1414H,
1402 9
1413 14