SCN5A Variant R222Q

Summary of observed carriers, functional annotations, and structural context for SCN5A R222Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

30%

2/12 effective observations

Estimated BrS1 penetrance

27%

3/12 effective observations

Total carriers

2

1 BrS1 · 1 LQT3 · 0 unaffected

R222Q 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 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 (%)
-3.9 0.995 -0.69 0.984 28 30

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
22710484 2012 2 0 0 2 DCM, conduction disease
22766342 2012 5 0 0 5 DCM
19412328 2008 1 0 0 1 DCM
20458009 2010 6 0 0 6 DCM
21167004 2010 6 0 0 6 DCM
21596231 2011 2 0 0 2 DCM
22999724 2012 7 0 0 7 DCM, ventricular ectopy, conduction abnormalities
19716085 2009 1 1 0 0
20129283 2010 1 0 1 0
29871609 2018 2 0 0 2 DCM
30059973 2018 1 1 0 0
Literature, cohort, and gnomAD – 2 0 1 1 –
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)
22710484 2012 CHO 110 -9 -7.3
22766342 2012 COS-7 122 -11.7 -5
19412328 2008
20458009 2010
25624448 2015
21167004 2010
21596231 2011
22999724 2012
24815523 2014 tsA201 -13.9 -6.7 69
19716085 2009
20129283 2010
29871609 2018
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 R222Q.
Neighbour residue Distance (Å) Observed variants
223 6 V223L,
856 10 V856L, V856L,
859 9
198 14
149 13
147 10
164 9 F164L, F164L, F164L,
209 14 N209S, N209T,
195 15
228 14 K228R,
227 13 L227P,
171 15
143 13
137 15 I137V,
142 14
156 13 W156R, W156R, W156X,
158 12 K158T,
197 13
229 15
163 13 c.486delC,
216 10 S216X, S216L,
851 12 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 8
196 12
169 14
852 11
854 13 c.2559delT,
222 0 R222X, R222Q, R222L,
224 8 L224F,
857 13 G857D,
150 14
157 13 T157I,
160 12 p.V160fs,
226 10 A226G, A226V,
205 12 c.612-2A>G, Y205X,
860 13 p.L860fsx89
206 10
166 13 A166T,
858 12 M858L, M858L,
144 8
217 9
855 9
199 11 S199T,
148 7
165 9
884 15
210 15 I210T,
204 6 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
162 12 Y162H, Y162C,
146 13 V146M, V146A,
203 8
208 10 E208K,
168 10
202 11 I202T,
141 11 I141V, I141N,
167 13
853 15
161 8 E161K, E161Q,
201 9
219 6 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 9 R225W, R225Q,
151 10
218 8
207 8
212 14 L212Q, L212P,
215 13 p.L215CfsX10,
200 7
145 10
140 12
220 7 T220I,