SCN5A Variant A226V

Summary of observed carriers, functional annotations, and structural context for SCN5A A226V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

1%

0/46 effective observations

Estimated BrS1 penetrance

12%

5/46 effective observations

Total carriers

36

4 BrS1 · 0 LQT3 · 32 unaffected

A226V is present in 27 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 1 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 (%)
-3.75 0.998 1.08 0.891 12 11

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
25829473 2015 3 0 1 0
11901046 2002 1 0 1 0
14967853 2004 4 0 1 0
28779003 2017 1 0 0 1 DCM
20129283 2010 2 0 2 0
Literature, cohort, and gnomAD – 36 32 0 4 –
Variant features alone – 15 14 0 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)
25829473 2015 tsA201 24
30050137 2018 tsA201 47 3.21 -0.16
11901046 2002
14967853 2004
28779003 2017
20129283 2010

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 A226V.
Neighbour residue Distance (Å) Observed variants
848 7 I848F,
223 6 V223L,
856 12 V856L, V856L,
240 14 V240M,
231 10 c.692_693delCA,
198 15
149 13
147 13
193 11 W193R, W193R, W193X,
164 13 F164L, F164L, F164L,
195 14
228 6 K228R,
138 9 M138I, M138I, M138I,
925 15 I925F
227 4 L227P,
143 11
171 14
137 12 I137V,
142 8
197 10
229 5
851 7 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 12
196 9
852 6
854 12 c.2559delT,
222 10 R222X, R222Q, R222L,
224 6 L224F,
845 10 c.2533delG,
857 15 G857D,
232 11 V232I, V232F,
134 15 N134S,
849 9
226 0 A226G, A226V,
858 15 M858L, M858L,
144 8
855 10
230 8 I230V, I230T, I230M,
199 13 S199T,
139 12 p.I137_C139dup,
148 10
884 14
204 15 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
236 14
146 12 V146M, V146A,
847 10
203 14
846 13 L846R,
192 14
168 12
233 12
194 14
141 6 I141V, I141N,
853 11
201 13
219 15 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 6 R225W, R225Q,
844 12 L844RfsX3,
850 11 V850M, c.2549_2550insTG,
200 10
145 7
140 11
220 13 T220I,