SCN5A Variant I1448L

Summary of observed carriers, functional annotations, and structural context for SCN5A I1448L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

7%

1/21 effective observations

Estimated BrS1 penetrance

21%

4/21 effective observations

Total carriers

11

1 BrS1 · 1 LQT3 · 9 unaffected

I1448L is present in 9 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 3 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 (%)
0.65 0.002 3.78 0.53 55 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
25163546 2015 1 0 0 1 DCM
27566755 2016 1 1 0 0
20129283 2010 1 0 1 0
Literature, cohort, and gnomAD – 11 9 1 1 –
Variant features alone – 15 12 0 3 – –

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)
25163546 2015
27566755 2016
20129283 2010

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 I1448L.
Neighbour residue Distance (Å) Observed variants
891 15 I891N, I891T,
888 9
1355 12
890 15 I890T,
896 15 C896S, C896S,
895 15 L895F,
1352 13
1445 8 Y1445H,
1457 14
1453 10
1455 10
1447 4
1444 9 L1444I,
1351 11 M1351V, M1351R,
1449 6 Y1449S, Y1449C,
1452 6
1429 11
806 14 V806M,
1450 7
887 14
1451 5 V1451L, V1451D,
886 13 H886P, H886Q, H886Q,
1458 15 S1458Y,
851 15 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
1348 11 F1348L, F1348L, F1348L,
1431 15 S1431C,
1422 15 M1422R,
892 10 F892I,
1356 13 c.4066_4068delTT,
1412 14 L1412F,
889 10
843 14 T843A,
1456 12
1459 14 c.4376_4379delTCTT
1425 10
1454 10
1446 6
1424 15 I1424V,
1448 0 I1448L, I1448T,
884 12
809 14
1421 14
885 9
847 13
1443 12 N1443S,
846 15 L846R,
879 15 W879R, W879R,
883 15
1415 13
1428 12 A1428S, A1428V,
850 14 V850M, c.2549_2550insTG,