SCN5A Variant S539Y Detail

We estimate the penetrance of LQTS for SCN5A S539Y around 14% and the Brugada syndrome penetrance around 12%. SCN5A S539Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S539Y is not present in gnomAD. S539Y 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 S539Y around 14% (0/10) and the Brugada syndrome penetrance around 12% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.736 9 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: - 0 0 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.

S539Y 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
524 15 c.1570_1571insG, S524Y,
525 14 S525G,
526 14 R526C, R526H,
527 13 G527R,
528 13 S528R,
529 12
530 11 F530V, F530S,
531 11 T531I, T531A,
532 10 F532L, F532C,
533 9 R533S, R533C, R533H,
534 8
535 8 R535G, R535Q, R535X,
536 7 D536H,
537 5
538 4 G538D,
539 0
540 4
541 5
542 7
543 8 F543L,
544 8
545 9
546 10
547 11
548 11
549 12
550 13
551 13 A551T, A551V,
552 14 G552R, G552W,
553 14 E553K, E553X,
554 15 S554I, S554N,