SCN5A Variant E1877K Detail

We estimate the penetrance of LQTS for SCN5A E1877K around 4% and the Brugada syndrome penetrance around 8%. SCN5A E1877K was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E1877K is present in 1 alleles in gnomAD. E1877K has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Non_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 (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A E1877K around 4% (0/11) and the Brugada syndrome penetrance around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.55 0.668 1.7 0.849 4 0
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 15 0 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.

E1877K has 33 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
1855 10
1875 7 M1875T, M1875K, p.M1875dup,
1872 9 K1872N,
1884 12 P1884L,
1878 6
1491 13 Q1491H,
1871 11
1856 12
1860 15 c.5577_5578dupAA,
1874 5
1862 13
1837 15
1863 13
1867 13
1858 14
1873 5 I1873V,
1879 8
1881 8
1877 0 E1877K,
1882 10
1885 14
1870 12 A1870T,
1883 12
1498 12 M1498V, M1498T, M1498R,
1839 11 D1839G,
1880 6 M1880V,
1866 15
1494 11
1838 13
1859 8
1869 11
1876 6
1868 14