SCN5A Variant S516A Detail

We estimate the penetrance of LQTS for SCN5A S516A around 2% and the Brugada syndrome penetrance around 25%. SCN5A S516A was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S516A is not present in gnomAD. S516A has been functionally characterized in 1 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 S516A around 2% (0/10) and the Brugada syndrome penetrance around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.38 0.114 -0.87 None 30 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
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
22514276 2012

S516A 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
501 15 D501G,
502 14
503 14 P503S,
504 13 R504T,
505 13 A505E,
506 12 M506K,
507 11 p.N507_L515dup,
508 11
509 10
510 9
511 8
512 8 T512I,
513 7 R513H, R513P, R513C, c.1537delC,
514 5 G514C,
515 4
516 0
517 4 R517S,
518 5
519 7 S519F,
520 8 M520R, M520V,
521 8 K521E, c.1562delA,
522 9 P522S,
523 10 R523S, R523C, R523H,
524 11 c.1570_1571insG, S524Y,
525 11 S525G,
526 12 R526C, R526H,
527 13 G527R,
528 13 S528R,
529 14
530 14 F530V, F530S,
531 15 T531I, T531A,