SCN5A Variant E1781D Detail

We estimate the penetrance of LQTS for SCN5A E1781D around 49% and the Brugada syndrome penetrance around 8%. SCN5A E1781D was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E1781D is present in 1 alleles in gnomAD. E1781D has been functionally characterized in 0 papers. This residue is located in a Mild_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 (0 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A E1781D around 49% (2/11) and the Brugada syndrome penetrance around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.78 0.995 4.81 0.629 12 71
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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 13 2 0 - -
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.

E1781D has 61 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 13 M414V,
1785 5
1778 5
1773 12
1653 15
1652 10 M1652T, M1652R,
1824 13 P1824A,
1777 5 V1777M, V1777L,
1650 14 L1650F,
1492 9
1504 15 K1504E,
1641 13
1477 14 K1477N,
1491 12 Q1491H,
1501 13 L1501V, p.L1501_K1505del,
1862 12
1779 7 T1779M,
1493 6 p.K1493del, K1493R, K1493X,
1858 13
1865 13
1478 15 K1478E,
1776 8
1787 6 S1787N,
1786 7 L1786Q, L1786R, c.5356_5357delCT,
1648 10
1861 13 V1861I, V1861F,
1495 11 Y1495S,
1649 11 A1649V,
1774 10 N1774D, c.5321_5324dupACTT,
1644 14 R1644C, R1644L, R1644H,
1496 7
1474 15
1481 14 G1481R, G1481V, G1481E,
1825 15 L1825P,
1781 0 E1781G, E1781D,
1789 11
1772 15 L1772V,
1499 12
1645 10 T1645M,
1488 14 T1488R,
1784 8 E1784K, E1784X,
1498 12 M1498R, M1498T, M1498V,
1780 6 E1780G,
1788 9 c.5361_5364delTGAG,
1651 15
1500 9 p.K1500del,
1791 10
1482 15
1792 14 D1792V, D1792Y, D1792N,
1783 7
1775 10 F1775V, p.F1775LfsX15,
1642 13 G1642E,
1497 8
1490 11
1790 10 D1790N, p.D1790del, D1790G,
1494 11
1647 15
1503 15 S1503Y,
1646 13
1489 10 E1489D,
1782 6