SCN5A Variant L224F

Summary of observed carriers, functional annotations, and structural context for SCN5A L224F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

45%

2/11 effective observations

Estimated BrS1 penetrance

15%

1/11 effective observations

Total carriers

1

0 BrS1 · 1 LQT3 · 0 unaffected

L224F 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 (%)
-3.57 0.999 1.12 0.924 18 44

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
30059973 2018 1 1 0 0
Literature, cohort, and gnomAD – 1 0 1 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)
30059973 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 L224F.
Neighbour residue Distance (Å) Observed variants
848 10 I848F,
223 4 V223L,
856 9 V856L, V856L,
859 12
231 14 c.692_693delCA,
198 13
193 10 W193R, W193R, W193X,
164 15 F164L, F164L, F164L,
195 10
228 9 K228R,
138 14 M138I, M138I, M138I,
925 14 I925F
227 6 L227P,
142 14
197 10
229 11
216 14 S216X, S216L,
851 10 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 6
196 6
852 6
854 12 c.2559delT,
222 8 R222X, R222Q, R222L,
224 0 L224F,
845 14 c.2533delG,
857 12 G857D,
191 15
849 10
226 6 A226G, A226V,
921 14
922 15 V922I,
860 13 p.L860fsx89,
858 14 M858L, M858L,
144 11
217 11
918 14
855 10
230 12 I230V, I230T, I230M,
199 9 S199T,
148 11
204 12 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
847 14
203 9
192 12
168 13
202 12 I202T,
194 13
141 11 I141V, I141N,
853 10
201 11
219 12 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 7 R225W, R225Q,
218 12
207 14
850 13 V850M, c.2549_2550insTG,
200 6
145 11
140 15
220 9 T220I,