SCN5A Variant E439D Detail

We estimate the penetrance of LQTS for SCN5A E439D around 3% and the Brugada syndrome penetrance around 32%. SCN5A E439D was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E439D is not present in gnomAD. E439D has been functionally characterized in 0 papers. This residue is located in a 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 (3 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 E439D around 3% (0/10) and the Brugada syndrome penetrance around 32% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.725 44 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: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 12 0 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.

E439D 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
424 15 I424M,
425 14 A425P, A425T,
426 14
427 13
428 13 E428K,
429 12 E429K, p.E429del,
430 11 K430E,
431 11
432 10
433 9 R433H, R433S, R433C,
434 8
435 8
436 7
437 5 A437V,
438 4 M438L, M438T,
439 0 E439K, E439V,
440 4
441 5 L441F,
442 7
443 8
444 8 E444fsX14,
445 9 H445D, H445Q, H445Y,
446 10 E446K,
447 11 c.1339-24G>A, A447G, A447S, c.1338+2T>A,
448 11
449 12 T449A, Y449C,
450 13
451 13
452 14 G452D,
453 14 V453M,
454 15