SCN5A Variant c.2437-5C>A

Summary of observed carriers, functional annotations, and structural context for SCN5A c.2437-5C>A. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

43%

3/14 effective observations

Estimated BrS1 penetrance

13%

1/14 effective observations

Total carriers

4

0 BrS1 · 2 LQT3 · 2 unaffected

c.2437-5C>A 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 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 18 48

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
28725320 2017 4 2 0 0
29672598 2018 1 0 0 1 SUDS
Literature, cohort, and gnomAD – 4 2 2 0 –
Variant features alone – 15 13 1 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)
28725320 2017
29672598 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 c.2437-5C>A.
Neighbour residue Distance (Å) Observed variants
811 8 R811G, R811H, c.2435_2436+3delTGGTAinsCGCCT,
808 12 R808P, R808H, R808C,
821 15
1351 11 M1351V, M1351R,
760 12 p.F760SfsX5,
780 13
1452 15
812 5 L812Q,
1350 12 I1350T, I1350L,
792 10
764 14 M764R, M764K,
791 8 L791F,
1344 13 F1344S, F1344L,
731 12 T731I,
806 12 V806M,
819 12
818 11
825 14
781 11 W781X,
1348 12 F1348L,
1349 14
788 6 I788V,
1346 13 L1346I, L1346P,
805 15 S805L,
782 14 N782T,
793 14 L793F,
728 15 V728I,
820 14
810 6
727 11
1456 15
734 11 c.2201dupT, M734V,
756 15
814 6 R814Q,
807 10
816 6 F816L, F816Y,
813 0 c.2436+12G>A, c.2437-5C>A,
757 13
786 11
1354 14
817 9 K817E,
809 7
815 7
790 11
1343 13
784 7 F784L,
796 15
785 9 D785N,
783 12 I783T,
730 12 N730K,
789 10 V789A, V789I,
753 14
1347 9
795 12
829 14
787 8
794 13