SCN5A Variant I529S Detail

We estimate the penetrance of LQTS for SCN5A I529S around 6% and the Brugada syndrome penetrance around 10%. SCN5A I529S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I529S is not present in gnomAD. I529S has been functionally characterized in 0 papers. This residue is located in a Non_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 (0 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 I529S around 6% (0/10) and the Brugada syndrome penetrance around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.643 5 5
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 15 0 0 - -
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.

I529S 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
514 15 G514C,
515 14
516 14
517 13 R517S,
518 13
519 12 S519F,
520 11 M520R, M520V,
521 11 K521E, c.1562delA,
522 10 P522S,
523 9 R523C, R523S, R523H,
524 8 S524Y, c.1570_1571insG,
525 8 S525G,
526 7 R526H, R526C,
527 5 G527R,
528 4 S528R,
529 0
530 4 F530V, F530S,
531 5 T531A, T531I,
532 7 F532C, F532L,
533 8 R533S, R533H, R533C,
534 8
535 9 R535X, R535Q, R535G,
536 10 D536H,
537 11
538 11 G538D,
539 12
540 13
541 13
542 14
543 14 F543L,
544 15