A1428S Summary

SCN5A A1428S was found in 6 papers (see below) with a total of 19 carriers: 8 had BrS1, 1 had LQT3, and 0 had other disease. A1428S is present in 8 out of 250628 alleles in gnomAD (minor allele frequency of 0.003192%). A1428S has been functionally characterized in 1 paper. Other variants at the same resdue are A1428D .A1428G .A1428P .A1428S .A1428T .A1428V . Given the functional data available, we estimate this variant has "Mild_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.

A1428S Reported Clinical Data

PMID Year Unaffected BrS LQT3 Other Other disease
2613687120150400
2323791220132010
2332162020130100
2770746820160200
2834178120170100
3005997320180010
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts.

A1428S 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
26136871 2015 HEK 61.8 2.23 -0.83 NA

A1428S 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 -2.85 probablydamaging 1 0.06294 2.86 0 0.937

A1428S has 66 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
878 11.5 R878C R878H
879 12.2 W879R W879R
885 14.4
886 13.8 H886P H886Q H886Q
889 12.8
1348 14.6
1349 14.2
1351 13.3
1352 10.3
1353 12.9 V1353M
1354 14
1355 8.8
1356 5.9
1357 10.5 A1357V
1358 10.7
1359 7
1360 6
1361 10.3
1362 10.1
1380 14.7 N1380K N1380K p.N1380del
1397 12.9
1398 10.1 V1398M
1399 14.7
1400 10.5
1401 10.4
1402 8.6
1403 12.5
1407 14.1
1408 12.5 G1408R G1408R
1411 11.3
1412 12.2
1414 14.1
1415 11.7
1420 12.1 G1420R G1420V
1421 11.5
1422 10.4
1423 9.5
1424 6.6
1425 5.9
1426 6.8
1427 3.6
1429 3.9
1430 5.4 D1430N
1431 4.9
1432 10.6 R1432S R1432S
1433 9.8 G1433W
1434 11.5
1436 13.7
1437 12.5
1438 9
1439 11.1
1440 11
1441 12.5
1442 11.4
1443 8.4 N1443S
1444 9.3
1445 10.7 Y1445H
1446 8.1
1447 10.3
1448 11.9 I1448L
1449 9.3 Y1449C
1450 8.2
1451 13.3
1452 14.6
1453 13.4
1454 14.7