SCN5A Variant L1255M Detail

We estimate the penetrance of LQTS for SCN5A L1255M around 2% and the Brugada syndrome penetrance around 12%. SCN5A L1255M was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L1255M is present in 1 alleles in gnomAD. L1255M has been functionally characterized in 0 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 L1255M around 2% (0/11) and the Brugada syndrome penetrance around 12% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.65 0.918 1.41 0.774 12 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: - 1 1 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.

L1255M has 29 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
1253 8 E1253G,
1211 14
1267 12
1252 6
1262 11 G1262S,
1283 13 L1283M,
1280 13
1247 12 T1247I,
1282 14 S1282A,
1259 7
1257 8
1256 5
1250 10
1275 12 D1275N,
1255 0 L1255M,
1251 6 V1251M,
1248 12
1279 10 V1279I,
1258 5
1254 5
1207 14
1276 11
1278 14 I1278N,
1272 13
1266 11
1260 10 A1260D,
1261 12
1249 10 V1249D,
1263 12