SCN5A Variant M1245I Detail

We estimate the penetrance of LQTS for SCN5A M1245I around 2% and the Brugada syndrome penetrance around 3%. SCN5A M1245I was found in a total of 3 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M1245I is present in 1 alleles in gnomAD. M1245I 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 (0 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 M1245I around 2% (0/13) and the Brugada syndrome penetrance around 3% (0/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
1 0.047 4.53 0.485 6 0
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
27554632 2017 9 0 0 7 CM
LITERATURE, COHORT, AND GNOMAD: - 3 3 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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)
27554632 2017

M1245I has 40 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 0 M1245I,
1218 10 S1218I, S1218T,
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 R1306H, R1306S,
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,