D1275N Summary

SCN5A D1275N was found in 24 papers (see below) with a total of 28 carriers: 3 had BrS1, 0 had LQT3, and 37 had other disease. D1275N is present in 2 out of 251372 alleles in gnomAD (minor allele frequency of 0.000796%). D1275N has been functionally characterized in 4 papers. Other variants at the same resdue are D1275A .D1275E .D1275E .D1275G .D1275H .D1275N .D1275V .D1275Y . Given the functional data available, we estimate this variant has "Partial_LOF" 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.

D1275N Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2038465120100000
2863796920170001AV conduction block
2457316420140000
1252211620035003Atrial standstill
1546664320040008Dilated Cardiomyopathy
15671429200515007DCM
1567143620050000
1668401820060001conduction defect, atrial arrythmia
2476280520142002SSS
2611153420150001SND, AF
2679838720160002SSS
2770746820160100
2053975720100000
1925120920090100
2182492120110000
2379181720130000
2674645720161000
28294644201700013BBBlock, AF
1599869020050000
2012928320100100
2012928320100100
2932597620180100
2957918920180001Afib
3005997320180040
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

D1275N 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
28637969 2017 HEK 77.3 10.1 2 NA
24573164 2014 HEK 87.5 -0.84 NA
12522116 2003 Xeno 88.7 3.3 -0.7 NA

D1275N 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 -4.87 probablydamaging 1 0.1168 -2.2 2 0.935

D1275N has 58 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
1207 14.3
1208 13.3 E1208K
1211 10.4
1212 12 p.I1212del
1214 12.8
1215 10.1 I1215V
1216 14.2
1218 13.9 S1218I
1219 14.6
1246 12.6
1247 11.9 T1247I
1249 11.2
1250 7.4
1251 10.6 V1251M
1252 12.2
1253 7.7
1254 6.9
1255 12.3
1256 12.4
1257 8.4
1258 10
1260 14.6
1261 12
1262 13.6 G1262S
1263 14
1265 14.7
1266 7.8
1267 10.4
1268 12.6
1269 9.5 N1269S
1270 8.7
1271 8
1272 5.5
1273 7.8
1274 4.5
1276 6.6
1277 6.8
1278 5.2 I1278N
1279 7 V1279I
1280 9.3
1281 10.4 V1281F
1282 10.6
1283 12.5
1284 15
1302 14.1
1303 14.4 R1303Q
1304 13.2 T1304M
1305 9.4
1306 9.3 R1306H
1307 10.8
1308 8.9 L1308F
1309 5.3 R1309H
1310 10.3
1311 10.7
1312 9.9
1313 12.1
1315 13.9
1316 14.2 R1316Q