SCN5A Variant N1269S Detail

We estimate the penetrance of LQTS for SCN5A N1269S around 59% and the Brugada syndrome penetrance around 12%. SCN5A N1269S was found in a total of 8 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 6 had LQTS. N1269S is present in 1 alleles in gnomAD. N1269S has been functionally characterized in 2 papers. This residue is located in a Mild_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 (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A N1269S around 59% (7/18) and the Brugada syndrome penetrance around 12% (2/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.6 0.23 3.21 0.624 15 36
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
22840528 2012 1 0 1 0
27566755 2016 6 6 0 0
LITERATURE, COHORT, AND GNOMAD: - 8 1 6 1 -
VARIANT FEATURES ALONE: - 15 13 1 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)
22840528 2012
27566755 2016

N1269S has 34 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 8
1328 13 V1328M,
1271 6 W1271C,
1315 13
1274 9
1258 12
1272 4
1270 4 A1270S,
1309 13 R1309H, R1309C,
1265 7
1313 14
1279 15 V1279I,
1316 14 R1316L, R1316Q,
1273 8 c.3816delG, W1273C,
1262 10 G1262S,
1324 14
1257 11
1268 5 T1268N, T1268S,
1275 9 D1275N,
1254 13
1260 14 A1260D,
1263 11
1253 14 E1253G,
1264 11 K1264N, K1264R,
1312 10
1311 13 L1311P,
1308 14 L1308F,
1269 0 N1269S,
1325 14 N1325S,
1276 11
1278 14 I1278N,
1266 6
1261 8
1277 12