SCN5A Variant K521E Detail

We estimate the penetrance of LQTS for SCN5A K521E around 0% and the Brugada syndrome penetrance around 21%. SCN5A K521E was found in a total of 2 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. K521E is present in 2 alleles in gnomAD. K521E has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 K521E around 0% (0/12) and the Brugada syndrome penetrance around 21% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.36 0.09 -1.11 0.552 33 1
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: - 2 2 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

K521E 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
506 15 M506K,
507 14 p.N507_L515dup,
508 14
509 13
510 13
511 12
512 11 T512I,
513 11 c.1537delC, R513P, R513C, R513H,
514 10 G514C,
515 9
516 8
517 8 R517S,
518 7
519 5 S519F,
520 4 M520R, M520V,
521 0 K521E, c.1562delA,
522 4 P522S,
523 5 R523S, R523C, R523H,
524 7 S524Y, c.1570_1571insG,
525 8 S525G,
526 8 R526C, R526H,
527 9 G527R,
528 10 S528R,
529 11
530 11 F530S, F530V,
531 12 T531A, T531I,
532 13 F532L, F532C,
533 13 R533H, R533S, R533C,
534 14
535 14 R535G, R535Q, R535X,
536 15 D536H,