SCN5A Variant I848F

Summary of observed carriers, functional annotations, and structural context for SCN5A I848F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

36%

2/12 effective observations

Estimated BrS1 penetrance

18%

2/12 effective observations

Total carriers

2

0 BrS1 · 1 LQT3 · 1 unaffected

I848F is present in 1 alleles 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 (%)
-3.96 1 1.69 0.961 27 36

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
26746457 2016 1 0 0 1 BBB, AV node disease
19716085 2009 1 1 0 0
Literature, cohort, and gnomAD – 2 1 1 0 –
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)
26746457 2016
19716085 2009

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 I848F.
Neighbour residue Distance (Å) Observed variants
891 12 I891N, I891T,
888 11
848 0 I848F,
223 10 V223L,
856 13 V856L, V856L,
895 13 L895F,
839 14 L839P,
842 10
240 11 V240M,
231 11 c.692_693delCA,
1455 15
149 14
193 13 W193R, W193R, W193X,
926 11
228 10 K228R,
138 13 M138I, M138I, M138I,
925 12 I925F,
227 7 L227P,
143 15
887 14
234 14 P234S,
1451 15 V1451L, V1451D
142 11
229 6
933 15
851 6 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
196 14
852 6
854 10 c.2559delT,
224 10 L224F,
845 5 c.2533delG,
857 15 G857D,
232 11 V232I, V232F,
892 13 F892I,
849 5
226 7 A226G, A226V,
921 15
922 13 V922I,
235 14 c.703+1G>A, G235R, G235R, c.704-1G>C,
840 11
843 9 T843A,
930 11 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
144 13
855 11
239 12 I239V, I239V ,
230 6 I230V, I230T, I230M,
148 13
929 14
884 13
841 11 p.N841TfsX2, N841K, N841K,
236 12
847 4
146 13 V146M, V146A,
846 7 L846R,
233 9
838 15
141 11 I141V, I141N,
853 9
225 12 R225W, R225Q,
844 6 L844RfsX3,
850 7 V850M, c.2549_2550insTG,
243 12
145 10
931 14