SCN5A Variant V1251M

Summary of observed carriers, functional annotations, and structural context for SCN5A V1251M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

0%

0/70 effective observations

Estimated BrS1 penetrance

2%

1/70 effective observations

Total carriers

60

0 BrS1 · 0 LQT3 · 60 unaffected

V1251M is present in 59 alleles 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 (%)
-2.27 0.999 -1.89 0.769 19 0

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
20129283 2010 1 0 0 0
Literature, cohort, and gnomAD – 60 60 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)
20129283 2010
32533946 2020 HEK 120 4.9 4.4

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 V1251M.
Neighbour residue Distance (Å) Observed variants
1267 14
1245 11 M1245I,
1281 12 V1281F, c.3840+1G>A,
1243 12 D1243N,
1274 15
1285 13
1258 9
1272 14
1252 5
1283 8 L1283M,
1309 13 R1309C, R1309H,
1259 13
1242 14
1251 0 V1251M,
1279 7 V1279I,
1207 15
1306 12 R1306S, R1306H,
1244 12 K1244E,
1286 10
1282 9 S1282A,
1246 10
1247 7 T1247I,
1257 10
1256 9
1275 11 D1275N,
1255 6 L1255M,
1254 6
1215 14 I1215V,
1260 14 A1260D,
1214 13 M1214T,
1253 7 E1253G,
1284 13
1211 13
1280 10
1250 6
1248 7
1287 14
1276 11
1278 11 I1278N,
1266 13
1249 6 V1249D,
1277 13