SCN5A Variant R225Q

Summary of observed carriers, functional annotations, and structural context for SCN5A R225Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

16%

1/15 effective observations

Estimated BrS1 penetrance

11%

1/15 effective observations

Total carriers

5

0 BrS1 · 1 LQT3 · 4 unaffected

R225Q is present in 4 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 (%)
-3.9 0.995 -3.86 0.979 15 20

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
28779003 2017 1 0 0 1 DCM
24631775 2014 1 0 0 1 SD
16922724 2006 1 1 0 0
Literature, cohort, and gnomAD – 5 4 1 0 –
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)
28779003 2017 mouse 67 0 0
24631775 2014
16922724 2006
24815523 2014 tsA201 -2.9 -4.2 185

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 R225Q.
Neighbour residue Distance (Å) Observed variants
848 12 I848F,
223 8 V223L,
856 14 V856L,
231 11 c.692_693delCA,
198 10
147 13
193 10 W193R, W193X,
164 10 F164L,
195 11
170 14 F170I,
228 6 K228R,
138 8 M138I,
227 7 L227P,
143 11
171 9
137 8 I137V,
142 10
197 6
229 8
163 14 c.486delC,
851 12 c.2552_2553dupGT, c.2550_2551dupGT, p.F851CfsX19, F851L,
221 11
196 7
169 12
189 15
852 11
222 9 R222X, R222L, R222Q,
224 7 L224F,
232 13 V232F, V232I,
133 13
160 15 p.V160fs,
191 14
134 12 N134S,
849 14
226 6 A226V, A226G,
205 15 Y205X, c.612-2A>G,
166 13 A166T,
144 8
855 13
172 12
230 11 I230M, I230V, I230T,
199 9 S199T,
139 11 p.I137_C139dup,
148 11
165 11
204 11 c.611+3_611+4dupAA, A204V, c.611+1G>A, A204T,
146 14 V146A, V146M,
203 11
192 13
136 13 L136P,
168 7
175 12 K175N,
202 12 I202T,
194 10
141 5 I141V, I141N,
188 14
135 14 M135V,
167 11
161 13 E161Q, E161K,
201 8
219 14 R219C, R219H, c.656_657insATTCA, p.R219HfsX11,
225 0 R225W, R225Q,
218 14
207 15
200 6
145 10
140 9
220 13 T220I,