SCN5A Variant M1245I

Summary of observed carriers, functional annotations, and structural context for SCN5A M1245I. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

2%

0/13 effective observations

Estimated BrS1 penetrance

3%

0/13 effective observations

Total carriers

3

0 BrS1 · 0 LQT3 · 3 unaffected

M1245I is present in 1 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 0 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 (%)
1 0.047 4.53 0.485 6 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
27554632 2017 9 0 0 7 CM
Literature, cohort, and gnomAD – 3 3 0 0 –
Variant features alone – 15 15 0 0 – –

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)
27554632 2017

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 M1245I.
Neighbour residue Distance (Å) Observed variants
1245 0 M1245I, M1245I, M1245I,
1218 10 S1218T, S1218I,
1217 10
1243 7 D1243N,
1216 15 L1216V,
1285 13
1220 14 G1220E,
1213 13
1210 12 F1210S,
1252 11
1283 14 L1283M
1241 5
1309 14 R1309H, R1309C,
1221 12 A1221V,
1242 5
1219 13 S1219N,
1251 11 V1251M,
1279 14 V1279I,
1239 10 L1239P,
1306 11 R1306S, R1306H,
1244 6 K1244E,
1286 12
1282 11 S1282A,
1235 14
1246 4
1247 7 T1247I,
1237 12 V1237F,
1289 14
1222 13 p.L1222LfsX7, L1222R,
1215 12 I1215V,
1214 9 M1214T,
1253 12 E1253G,
1211 13
1250 9
1240 10 E1240Q,
1248 7
1278 15 I1278N,
1238 10
1249 7 V1249D,
1303 12 R1303Q, R1303W,