SCN5A Variant E1780G Detail

We estimate the penetrance of LQTS for SCN5A E1780G around 18% and the Brugada syndrome penetrance around 41%. SCN5A E1780G was found in a total of 1 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. E1780G is not present in gnomAD. E1780G has been functionally characterized in 2 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 (3 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 E1780G around 18% (1/11) and the Brugada syndrome penetrance around 41% (4/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.47 1 -3.51 0.899 49 26
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
24613995 2014 1 0 0 1 irritable bowel syndrome
25650408 2015 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 1 3 - -
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
24613995 2014 HEK 62 3.6 2.1 341

E1780G has 53 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
414 9 M414V,
1785 8
1778 6
1773 11
249 14 K249X,
1652 14 M1652R, M1652T,
1777 6 V1777M, V1777L,
1487 14 M1487K, M1487L,
418 10 E418K,
1492 10
417 11
1477 14 K1477N,
1491 13 Q1491H,
1862 14
1779 4 T1779M,
412 15 V412D,
1493 7 K1493R, K1493X, p.K1493del,
1865 14
1478 14 K1478E,
1776 6
1787 11 S1787N,
1786 12 c.5356_5357delCT, L1786R, L1786Q,
1648 14
415 12 A415T,
1495 15 Y1495S,
1649 13 A1649V,
1774 11 c.5321_5324dupACTT, N1774D,
420 15
1496 11
1474 13
1781 6 E1781D, E1781G,
1772 13 L1772V,
1645 12 T1645M,
1784 8 E1784X, E1784K,
1488 11 T1488R,
410 12 A410V,
1780 0 E1780G,
1788 15 c.5361_5364delTGAG,
1500 14 p.K1500del,
413 12 A413E, A413T,
1783 5
422 14
1775 9 F1775V, p.F1775LfsX15,
1642 14 G1642E,
421 12
1497 13
1490 9
1790 15 D1790N, p.D1790del, D1790G,
1494 14
411 13 V411M,
1646 13
1489 8 E1489D,
1782 6