E1225K Summary

SCN5A E1225K was found in 18 papers (see below) with a total of 14 carriers: 11 had BrS1, 1 had LQT3, and 0 had other disease. E1225K is present in 1 out of 249528 alleles in gnomAD (minor allele frequency of 0.000401%). E1225K has been functionally characterized in 1 paper. Other variants at the same resdue are E1225A .E1225D .E1225D .E1225G .E1225K .E1225Q .E1225V .G1225K . 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 Hotspot region for BrS1 and in a Non_Hotspot region for Long QT syndrome.

E1225K Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
1210694320020100
1496155220031200
1584047620050010
1740415820070100
2284052820120200
2332162020130100
2472145620140100
2692176420160100
2694133920160100
2834178120170200
2878133020170100
2012928320100100
2012928320100100
2012928320100100
2012928320100100
2957414020180200
3005997320180030
3253394620200000
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

E1225K 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 36 3.9 11.5 0.538461538 NA

E1225K 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 -3.91 probablydamaging 1 0.05085 -2.67 -4 0.95

E1225K has 56 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
1217 13.8
1218 10.9 S1218I
1219 10.4
1220 9.5
1221 7.2 A1221V
1222 5.7
1223 6.7
1224 7.2
1226 4.2
1227 8
1228 8.9 Y1228C Y1228H
1229 5.5
1230 9.9 E1230K
1231 11.5 E1231K
1232 14.5 R1232Q R1232W
1233 12.1
1234 11.5
1235 7.1
1236 8.4 K1236R
1237 11.2
1238 10.5
1239 6.1 L1239P
1240 9.2 E1240Q
1241 14
1242 11
1243 11.1 D1243N
1246 14.3
1285 14.7
1299 13.1
1300 12.6
1301 9.2
1302 13
1303 8.1 R1303Q
1304 10 T1304M
1305 14.2
1306 12 R1306H
1307 12.7
1669 12.5
1670 14.3
1672 11.3 S1672Y
1673 8.4
1674 12.8 F1674V
1675 11.8
1676 8.4 M1676I M1676I M1676I
1677 9.1
1678 12.9 N1678S
1679 14.1
1680 11.9 A1680T
1681 13.4 Y1681F
1694 13.7
1695 11.8
1696 10.1
1697 10.3
1698 13.5 A1698T
1699 14.7
1700 13.5