SCN5A Variant S1218I Detail

We estimate the penetrance of LQTS for SCN5A S1218I around 3% and the Brugada syndrome penetrance around 53%. SCN5A S1218I was found in a total of 3 carriers in 1 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. S1218I is not present in gnomAD. S1218I has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (3 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A S1218I around 3% (0/13) and the Brugada syndrome penetrance around 53% (6/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.86 1 -5.97 0.961 45 6
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
23424222 2013 3 0 3 0
LITERATURE, COHORT, AND GNOMAD: - 3 0 0 3 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
23424222 2013 CHO 0

S1218I has 57 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
1245 10 M1245I,
1218 0 S1218I, S1218T,
1281 15 c.3840+1G>A, V1281F,
1304 11 T1304M,
1217 4
1243 10 D1243N,
1216 6 L1216V,
1220 5 G1220E,
1673 11
1213 9
1210 12 F1210S,
1241 11
1309 9 R1309H, R1309C,
1226 14
1669 11
1221 5 A1221V,
1242 7
1219 4 S1219N,
1672 15 S1672Y,
1313 14
1279 15 V1279I,
1239 9 L1239P,
1310 10
1306 7 R1306S, R1306H,
1244 13 K1244E,
1305 12
1246 6
1235 13
1282 13 S1282A,
1302 15 p.L1302Vfs18,
1247 12 T1247I,
1237 15 V1237F,
1307 9
1223 9 c.3667delG,
1697 14
1275 14 D1275N,
1222 6 p.L1222LfsX7, L1222R,
1215 6 I1215V,
1301 14
1214 7 M1214T,
1212 11 p.I1212del,
1253 14 E1253G,
1211 11
1311 14 L1311P,
1308 12 L1308F,
1250 10
1224 10
1670 13
1209 14 T1209R,
1240 12 E1240Q,
1248 14
1225 11 E1225K, G1225K,
1278 12 I1278N,
1238 11
1249 11 V1249D,
1303 9 R1303Q, R1303W,
1666 14