D1243N Summary

SCN5A D1243N was found in 9 papers (see below) with a total of 47 carriers: 5 had BrS1, 0 had LQT3, and 0 had other disease. D1243N is present in 41 out of 282620 alleles in gnomAD (minor allele frequency of 0.014507%). D1243N has been functionally characterized in 1 paper. Other variants at the same resdue are D1243A .D1243E .D1243E .D1243G .D1243H .D1243N .D1243V .D1243Y . Given the functional data available, we estimate this variant has "Normal" in vitro character. (LOF and GOF denote loss-of-function and gain-of-function, respectively). This residue is located in a Mild_Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

D1243N Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2288591720120200
2617311120150100
2692176420160200
2674645720161000
2012928320100100
2012928320100100
2012928320100500
2932597620180300
3253394620200000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D1243N Reported Functional Data

Peak current and late current are relative % to 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.

PMID Year Cell type Peak current V0.5 act V0.5 inact Rec from inact Late current
32533946 2020 HEK 114.7 5.7 7.8 0.5 NA

D1243N Predictions

PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 is 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. PAM scores reflect the chemistry difference between WT and variant amino acid (more negative being greater difference between the two). BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected.

SIFT Sift Score PROVEAN Score Polyphen2 Polyphen2 Score eaRate blastPssm pamScore REVEL
Damaging 0 -4.89 probablydamaging 1 0.08026 4.97 2 0.924

D1243N has 54 neighbors within 15 ångströms that have been found in individuals.

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.

ResidueNumber Distance(Å) Variants
1214 13
1215 13.2 I1215V
1217 13
1218 9.7 S1218I
1219 12.4
1220 13.5
1221 11.2 A1221V
1222 9.9
1223 14.6
1225 11.1 E1225K
1226 14.8
1229 13.7
1235 12.4
1236 11.6 K1236R
1237 10.6
1238 10.1
1239 7.3 L1239P
1240 5.2 E1240Q
1241 7.7
1242 4.5
1244 5.8
1245 7.3 M1245I M1245I M1245I
1246 6.9
1247 5.9 T1247I
1248 8.6
1249 10.4
1250 9.5
1251 12.4 V1251M
1253 14.7
1278 11.4 I1278N
1279 11.2 V1279I
1280 13.2
1281 9.8 V1281F
1282 6.9
1283 10.1
1284 10.4
1285 6.6
1286 8.2
1287 11.8
1288 10.9
1289 9.5
1290 14.2
1298 14.7 P1298L
1299 10.6
1300 13.9
1301 10.9
1302 10.4
1303 5.7 R1303Q
1304 11.2 T1304M
1305 12.2
1306 7.4 R1306H
1307 13.4
1309 13.8 R1309H
1673 14.9