SCN5A Variant R219H

Summary of observed carriers, functional annotations, and structural context for SCN5A R219H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

1%

0/11 effective observations

Estimated BrS1 penetrance

18%

1/11 effective observations

Total carriers

1

0 BrS1 · 0 LQT3 · 1 unaffected

R219H has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Non_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 (%)
-4.88 0.999 -3.36 0.989 23 2

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
22675453 2012 3 0 0 3 DCM
24762805 2014 2 0 0 1 SSS, DCM
Literature, cohort, and gnomAD – 1 1 0 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)
22675453 2012 tsA201 100 -2.49 -1.42 100
30218094 2018 hiPSC 105 -1.1 1.3 92
24762805 2014

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 R219H.
Neighbour residue Distance (Å) Observed variants
154 14 P154L,
223 9 V223L,
856 10 V856L, V856L,
862 11
859 5
149 13
147 11
164 13 F164L, F164L, F164L,
209 13 N209S, N209T,
863 11
156 10 W156R, W156R, W156X,
864 14
158 11 K158T,
216 6 S216X, S216L,
851 15 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
221 9
852 14
854 13 c.2559delT,
222 6 R222X, R222Q, R222L,
224 12 L224F,
213 12
155 15
857 11 G857D,
150 15
157 13 T157I,
882 15
160 14 p.V160fs,
881 14
226 15 A226G, A226V,
205 14 c.612-2A>G, Y205X,
860 10 p.L860fsx89,
206 11
214 12
858 10 M858L, M858L,
211 13
144 12
217 7
855 10
199 15 S199T,
148 9
165 13
884 15
210 12 I210T,
204 9 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
162 13 Y162H, Y162C,
203 10
208 11 E208K,
168 15
202 14 I202T,
152 13 D152N,
161 9 E161K, E161Q,
201 13
219 0 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 14 R225W, R225Q,
151 9
218 6
207 7
212 10 L212Q, L212P,
215 10 p.L215CfsX10,
200 11
145 14
861 13 p.F861WfsX90, c.2582_2583delTT
220 6 T220I,