SCN5A Variant T1290S Detail

We estimate the penetrance of LQTS for SCN5A T1290S around 9% and the Brugada syndrome penetrance around 30%. SCN5A T1290S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T1290S is not present in gnomAD. T1290S 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 (2 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 T1290S around 9% (0/10) and the Brugada syndrome penetrance around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.575 41 9
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 13 0 2 - -
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.

T1290S has 23 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
1292 7
1284 11
1291 5
1298 13 P1298L,
1283 12 L1283M,
1247 15 T1247I,
1282 14 S1282A,
1288 5 A1288G,
1289 5
1297 11
1243 14 D1243N,
1240 14 E1240Q,
1248 15
1296 13 M1296T,
1285 9
1287 6
1299 12 c.3894delC,
1290 0
1293 12 F1293S,
1244 13 K1244E,
1286 8
1294 11 A1294G,
1295 9 E1295K,