SCN5A Variant V294M

Summary of observed carriers, functional annotations, and structural context for SCN5A V294M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

1%

0/19 effective observations

Estimated BrS1 penetrance

11%

2/19 effective observations

Total carriers

9

1 BrS1 · 0 LQT3 · 8 unaffected

V294M is present in 8 alleles in gnomAD. This residue resides in a Non_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 (%)
-0.1 0.973 0.46 0.57 8 4

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
11901046 2002 1 0 1 0
25163546 2015 1 0 0 1 DCM
Literature, cohort, and gnomAD – 9 8 0 1 –
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)
11076825 2000
11901046 2002
25163546 2015

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 V294M.
Neighbour residue Distance (Å) Observed variants
279 15
280 14 C280Y,
281 14 V281M,
282 13 R282C, R282H,
283 13
284 12
285 11 T285K,
286 11 A286V, A286S,
287 10
288 9 N288S,
289 8 G289S,
290 8 p.T290_G292del,
291 7 N291S, p.N291TfsX52, N291H, N291K, p.N291_S293dup, N291K
292 5 G292S,
293 4
294 0 V294M,
295 4 E295K,
296 5
297 7
298 8 G298S, G298D,
299 8 L299M, L299F, L299F,
300 9 V300I,
301 10
302 11
303 11
304 12
305 13 D305N,
306 13 L306F, L306V,
307 14
308 14
309 15 S309N, S309C,