SCN5A Variant R1303Q Detail

We estimate the penetrance of LQTS for SCN5A R1303Q around 6% and the Brugada syndrome penetrance around 8%. SCN5A R1303Q was found in a total of 2 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R1303Q is present in 2 alleles in gnomAD. R1303Q has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (0 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 R1303Q around 6% (0/12) and the Brugada syndrome penetrance around 8% (0/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.53 1 -2.89 0.925 4 11
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: - 2 2 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

R1303Q has 68 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
1245 12 M1245I,
1218 9 S1218I, S1218T,
1297 15
1281 8 c.3840+1G>A, V1281F,
1304 6 T1304M,
1217 14
1243 6 D1243N,
1274 15
1216 15 L1216V,
1285 8
1299 9 c.3894delC,
1220 12 G1220E,
1673 10
1675 14
1298 13 P1298L,
1283 12 L1283M,
1241 12
1309 13 R1309H, R1309C,
1226 11
1288 12 A1288G,
1669 14
1221 10 A1221V,
1242 8
1676 13 M1676T, M1676I,
1219 10 S1219N,
1672 14 S1672Y,
1279 12 V1279I,
1239 8 L1239P,
1310 14
1306 6 R1306S, R1306H,
1244 11 K1244E,
1286 12
1305 8
1282 8 S1282A,
1246 10
1235 13
1302 6 p.L1302Vfs18,
1247 10 T1247I,
1237 13 V1237F,
1307 10
1289 13
1678 14 N1678S,
1223 11 c.3667delG,
1275 14 D1275N,
1222 7 p.L1222LfsX7, L1222R,
1300 10
1674 12 F1674V,
1229 12
1215 13 I1215V,
1301 6
1214 15 M1214T,
1284 10
1280 13
1677 11
1308 12 L1308F,
1250 11
1224 13
1670 13
1240 8 E1240Q,
1248 14
1225 8 E1225K, G1225K,
1287 14
1278 10 I1278N,
1238 13
1236 12 K1236R, K1236N,
1249 14 V1249D,
1277 14
1303 0 R1303Q, R1303W,