SCN5A Variant A1416E Detail

We estimate the penetrance of LQTS for SCN5A A1416E around 22% and the Brugada syndrome penetrance around 48%. SCN5A A1416E was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. A1416E is not present in gnomAD. A1416E has been functionally characterized in 1 papers. This residue is located in a 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 (4 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 A1416E around 22% (1/11) and the Brugada syndrome penetrance around 48% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.77 1 -3.49 0.96 60 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
25650408 2015 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 10 1 4 - -
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)
25650408 2015

A1416E has 74 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
896 9 C896S,
895 13 L895F,
1417 4
1765 15
1406 15 G1406R, G1406E,
1340 15 V1340I,
1457 6
1453 7
1455 10
1757 13
1449 12 Y1449C, Y1449S,
1452 12
1756 11 I1756V,
1461 9 T1461S,
1711 13 c.5131delG,
1344 13 F1344L, F1344S,
1450 10
1411 9
1451 11 V1451L, V1451D,
1407 14
934 15
1458 5 S1458Y,
1410 11
1714 12 D1714G,
897 12 G897E, G897R,
1348 11 F1348L,
1464 13 L1464P, c.4389_4396delCCTCTTTA,
1423 14 D1423H,
927 15 N927S, N927K,
1349 13
1753 13 T1753A,
1422 12 M1422R,
1346 14 L1346P, L1346I,
1418 5
892 12 F892I,
1712 13 G1712C, G1712S,
1341 11
898 12
893 13 R893H, R893C,
1462 7
1412 7 L1412F,
1759 15 S1759C,
1408 12 G1408R,
1709 14 p.T1709del, T1709R, T1709M,
1420 10 G1420R, G1420P, G1420D, G1420V,
1456 11
1459 9 c.4376_4379delTCTT,
1460 12 F1460L,
1425 12
1713 10
1454 6
1338 14 L1338V,
1424 11 I1424V,
1409 10 Y1409C, Y1409X,
1400 13 V1400I,
1421 8
1345 8 W1345C,
1337 15
1717 15 L1717P,
1342 13
1416 0 c.4245+1G>C, A1416E, c.4245+1G>A, A1416G, c.4245+2T>A,
1465 12 p.F1465_L1480dup,
1760 10
1752 15
1761 11 c.5280delG, L1761F, L1761H,
1347 15
1710 10 S1710L,
1415 4
1419 8 K1419E,
1414 7 Q1414H,
931 14
1402 14
1463 10 N1463Y,
1413 6