SCN5A Variant c.4438-1C>T

Summary of observed carriers, functional annotations, and structural context for SCN5A c.4438-1C>T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

18%

1/12 effective observations

Estimated BrS1 penetrance

30%

3/12 effective observations

Total carriers

2

1 BrS1 · 0 LQT3 · 1 unaffected

c.4438-1C>T has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 2 individuals for Brugada syndrome and 1 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 34 32

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
22633666 2012 2 0 1 0
Literature, cohort, and gnomAD – 2 1 0 1 –
Variant features alone – 15 12 1 2 – –

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)
22633666 2012

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 c.4438-1C>T.
Neighbour residue Distance (Å) Observed variants
1659 14
1480 0 c.4438-1C>T, c.4437+5G>A,
1773 12
1653 14
1472 13 N1472S, p.N1472del,
1315 15
1652 14 M1652T, M1652R,
1777 14 V1777L, V1777L, V1777M,
1485 15
1320 13 M1320I, M1320I, M1320I,
1492 12
1656 12
1477 6 K1477N, K1477N,
1478 8 K1478E,
1329 15 G1329S,
1769 15
1319 10 G1319V,
1495 12 Y1495S,
1774 13 N1774D, c.5321_5324dupACTT,
1479 6
1473 11 F1473C, F1473S,
1496 12
1474 11
1324 13
1481 4 G1481R, G1481V, G1481E, G1481R,
1317 14 F1317C,
1318 10
1499 13
1321 9 R1321K,
1323 11 V1323G,
1770 13 I1770V,
1482 7
1322 7 c.3963+2T>C, c.3963+4A>G,
1326 12 A1326S,
1476 6 Q1476X, Q1476R,
1484 12
1655 14
1475 9 Q1475L, p.Q1475NfsX6,
1483 11 Q1483H, Q1483H,
1325 10 N1325S,