SCN5A Variant F1473S Detail

We estimate the penetrance of LQTS for SCN5A F1473S around 75% and the Brugada syndrome penetrance around 15%. SCN5A F1473S was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. F1473S is not present in gnomAD. F1473S has been functionally characterized in 2 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (3 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A F1473S around 75% (4/11) and the Brugada syndrome penetrance around 15% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.67 0.975 -5.77 0.969 2 90
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
26496715 2016 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 11 3 1 - -
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)
26496715 2016
20339117 2010 HEK 20 4.38 18.94 2156

F1473S has 66 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
1328 11 V1328M,
939 13 L939F,
1659 13
1480 11 c.4438-1C>T, c.4437+5G>A,
1773 7
1765 10
943 14 S943N,
1653 12
1472 5 N1472S, p.N1472del,
1771 10 I1771T,
1652 14 M1652R, M1652T,
1777 13 V1777L, V1777M,
1320 12 M1320I,
1764 12 c.5290delG, V1764F,
409 15 L409V, L409P,
1333 13
1656 10
1477 6 K1477N,
1471 8
1762 11 p.I1762del, I1762M,
1470 6
1466 10 c.4396_4397insG,
1478 10 K1478E,
1776 12
944 15
1767 11 Y1767C,
1660 11 I1660V, I1660S,
1329 10 G1329S,
1769 5
1766 6 M1766V, M1766T, M1766L,
1319 11 G1319V,
1768 9 I1768V,
1774 10 c.5321_5324dupACTT, N1774D,
1479 10
1473 0 F1473C, F1473S,
1334 13 I1334V,
1468 9 V1468A, V1468F,
1663 14
1657 11
1474 7
1324 10
1481 13 G1481V, G1481E, G1481R,
1327 9
1330 9 A1330D, A1330T, A1330P,
1772 9 L1772V,
1321 14 R1321K,
1323 7 V1323G,
410 15 A410V,
1770 6 I1770V,
1482 14
1322 7 c.3963+2T>C, c.3963+4A>G,
1326 6 A1326S,
1763 11 V1763L, V1763M,
1332 14 P1332Q, P1332L,
1465 13 p.F1465_L1480dup,
1467 10
1476 6 Q1476R, Q1476X,
1775 14 F1775V, p.F1775LfsX15,
1661 15 G1661R, G1661E,
1331 13 I1331V,
1761 15 L1761H, c.5280delG, L1761F,
1655 14
1475 8 Q1475L, p.Q1475NfsX6,
1469 6 I1469V,
406 14 N406K, N406S,
1325 9 N1325S,