SCN5A Variant V223L

Summary of observed carriers, functional annotations, and structural context for SCN5A V223L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

11%

0/12 effective observations

Estimated BrS1 penetrance

46%

5/12 effective observations

Total carriers

2

2 BrS1 · 0 LQT3 · 0 unaffected

V223L has not been reported in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Mild_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 (%)
-2.93 0.983 1.32 0.944 48 17

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
20129283 2010 2 0 2 0
Literature, cohort, and gnomAD – 2 0 0 2 –
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)
20129283 2010
32533946 2020 HEK 34 -2.3 -3

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 V223L.
Neighbour residue Distance (Å) Observed variants
891 14 I891N, I891T,
888 14
848 10 I848F,
223 0 V223L,
856 7 V856L, V856L,
862 15
859 9
149 12
147 12
193 14 W193R, W193R, W193X,
164 13 F164L, F164L, F164L,
195 14
228 11 K228R,
138 14 M138I, M138I, M138I,
227 8 L227P,
143 13
887 13
142 12
197 12
229 11
216 13 S216X, S216L,
851 7 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 7
196 10
852 5
854 9 c.2559delT,
222 6 R222X, R222Q, R222L,
224 4 L224F,
845 14 c.2533delG,
857 10 G857D,
150 15
881 15
849 11
226 6 A226G, A226V,
921 15
922 15 V922I
860 11 p.L860fsx89,
858 10 M858L, M858L,
144 8
217 11
918 14
855 6
230 13 I230V, I230T, I230M,
199 12 S199T,
148 7
165 14
884 12
204 11 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
146 12 V146M, V146A,
847 13
203 11
168 13
202 14 I202T,
141 10 I141V, I141N,
853 9
161 13 E161K, E161Q,
201 12
219 9 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 8 R225W, R225Q,
151 12
218 11
207 14
850 11 V850M, c.2549_2550insTG,
200 8
145 8
140 13
861 14 p.F861WfsX90, c.2582_2583delTT,
220 7 T220I,