SCN5A Variant c.612-2A>G

Summary of observed carriers, functional annotations, and structural context for SCN5A c.612-2A>G. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

2%

0/18 effective observations

Estimated BrS1 penetrance

36%

6/18 effective observations

Total carriers

8

3 BrS1 · 0 LQT3 · 5 unaffected

c.612-2A>G has not been reported in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Non_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 (%)
NA NA NA None 47 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
20031634 2009 6 0 3 0
20129283 2010 1 0 1 0
29672598 2018 3 0 0 1 SUDS
Literature, cohort, and gnomAD – 8 5 0 3 –
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)
20031634 2009
20129283 2010
29672598 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 c.612-2A>G.
Neighbour residue Distance (Å) Observed variants
198 12
164 14 F164L, F164L, F164L,
209 6 N209S, N209T,
170 14 F170I,
171 14
158 15 K158T,
197 14
163 13 c.486delC,
169 8
222 12 R222X, R222Q, R222L,
205 0 c.612-2A>G, Y205X,
206 5
166 10 A166T,
211 12
217 14
172 11
199 11 S199T,
165 8
210 11 I210T,
204 6 A204T, c.611+1G>A, c.611+3_611+4dupAA, A204V,
162 10 Y162H, Y162C,
203 9
208 6 E208K,
168 11
202 6 I202T,
167 13
161 12 E161K, E161Q,
201 7
219 14 p.R219HfsX11, R219C, c.656_657insATTCA, R219H,
225 15 R225W, R225Q
218 10
207 7
212 14 L212Q, L212P,
173 13
200 11