SCN5A Variant E636K Detail

We estimate the penetrance of LQTS for SCN5A E636K around 9% and the Brugada syndrome penetrance around 10%. SCN5A E636K was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E636K is present in 1 alleles in gnomAD. E636K has been functionally characterized in 0 papers. This residue is located in a Non_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 (1 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 E636K around 9% (0/11) and the Brugada syndrome penetrance around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.78 0.011 -0.67 0.516 5 16
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 14 0 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.

E636K has 31 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
621 15
622 14
623 14 M623T,
624 13 L624Q,
625 13 E625Q, E625D, c.1872dupA,
626 12
627 11 P627L,
628 11 P628R,
629 10 D629Y,
630 9 T630M,
631 8 p.T631VfsX101, c.1890G>A, c.1890+5G>A,
632 8 T632M,
633 7
634 5 S634L, S634W,
635 4
636 0 E636K,
637 4 P637L,
638 5 G638D,
639 7 G639A, G639R,
640 8 P640A, P640S, P640L,
641 8
642 9
643 10
644 11
645 11
646 12 c.1936delC, p.Q646RfsX5,
647 13 A647V, A647S, A647D,
648 13 P648L,
649 14 C649R, C649Y,
650 14
651 15 D651H, c.1950_1953delAGAT,