SCN5A Variant V1251M Detail

We estimate the penetrance of LQTS for SCN5A V1251M around 0% and the Brugada syndrome penetrance around 2%. SCN5A V1251M was found in a total of 60 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V1251M is present in 59 alleles in gnomAD. V1251M has been functionally characterized in 2 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 (1 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 V1251M around 0% (0/70) and the Brugada syndrome penetrance around 2% (1/70).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.27 0.999 -1.89 0.769 19 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
20129283 2010 1 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 60 60 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 1 - -
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)
20129283 2010
32533946 2020 HEK 120 4.9 4.4

V1251M has 42 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 14
1245 11 M1245I,
1281 12 c.3840+1G>A, V1281F,
1243 12 D1243N,
1274 15
1285 13
1258 9
1272 14
1252 5
1283 8 L1283M,
1309 13 R1309H, R1309C,
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