SCN5A Variant L1308R Detail

We estimate the penetrance of LQTS for SCN5A L1308R around 5% and the Brugada syndrome penetrance around 13%. SCN5A L1308R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L1308R is not present in gnomAD. L1308R has been functionally characterized in 0 papers. This residue is located in a Non_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 L1308R around 5% (0/10) and the Brugada syndrome penetrance around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.902 9 2
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 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.

L1308R has 61 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
1271 9 W1271C,
1218 12 S1218I, S1218T,
1281 12 c.3840+1G>A, V1281F,
1304 7 T1304M,
1315 12
1274 6
1216 12 L1216V,
1314 11 c.3940_3941delCT,
1220 14 G1220E,
1673 10
1675 14
1666 9
1272 12
1754 14
1270 11 A1270S,
1309 7 R1309H, R1309C,
1669 10
1671 10
1221 15 A1221V,
1668 14 M1668T,
1219 10 S1219N,
1672 12 S1672Y,
1313 11
1279 13 V1279I,
1310 6
1306 8 R1306H, R1306S,
1665 14
1305 5
1273 12 c.3816delG, W1273C,
1246 15
1282 13 S1282A,
1663 13
1302 12 p.L1302Vfs18,
1324 14
1327 15
1307 4
1758 14 I1758V, p.I1758del,
1223 14 c.3667delG,
1275 9 D1275N,
1222 12 p.L1222LfsX7, L1222R,
1674 10 F1674V,
1215 10 I1215V,
1301 12
1214 15 M1214T,
1212 13 p.I1212del,
1253 15 E1253G,
1211 14
1312 11
1280 14
1751 15
1311 6 L1311P,
1677 15
1308 0 L1308F,
1250 13
1670 7
1269 14 N1269S,
1276 13
1278 8 I1278N,
1277 10
1667 10 V1667I,
1303 12 R1303Q, R1303W,