SCN5A Variant M1254V Detail

We estimate the penetrance of LQTS for SCN5A M1254V around 4% and the Brugada syndrome penetrance around 32%. SCN5A M1254V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M1254V is not present in gnomAD. M1254V has been functionally characterized in 0 papers. This residue is located in a 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 M1254V around 4% (0/10) and the Brugada syndrome penetrance around 32% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.966 42 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
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.

M1254V has 46 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
1267 10
1271 14 W1271C,
1281 12 c.3840+1G>A, V1281F,
1274 11
1258 5
1272 9
1270 14 A1270S,
1252 7
1283 11 L1283M,
1309 11 R1309H, R1309C,
1259 10
1265 15
1251 6 V1251M,
1279 6 V1279I,
1207 13
1306 13 R1306S, R1306H,
1286 15
1305 15
1273 11 W1273C, c.3816delG,
1282 11 S1282A,
1246 13
1262 11 G1262S,
1247 10 T1247I,
1257 5
1268 14 T1268N, T1268S,
1256 7
1275 7 D1275N,
1255 5 L1255M,
1254 0
1215 14 I1215V,
1260 11 A1260D,
1263 11
1214 14 M1214T,
1253 5 E1253G,
1211 11
1280 9
1250 7
1248 12
1269 13 N1269S,
1276 7
1278 9 I1278N,
1266 7
1261 11
1249 9 V1249D,
1208 14 E1208X, E1208K,
1277 11