SCN5A Variant D536N Detail

We estimate the penetrance of LQTS for SCN5A D536N around 31% and the Brugada syndrome penetrance around 7%. SCN5A D536N was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D536N is not present in gnomAD. D536N has been functionally characterized in 0 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A D536N around 31% (1/10) and the Brugada syndrome penetrance around 7% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.495 2 41
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 1 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.

D536N 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
521 15 K521E, c.1562delA,
522 14 P522S,
523 14 R523S, R523C, R523H,
524 13 c.1570_1571insG, S524Y,
525 13 S525G,
526 12 R526C, R526H,
527 11 G527R,
528 11 S528R,
529 10
530 9 F530S, F530V,
531 8 T531I, T531A,
532 8 F532C, F532L,
533 7 R533S, R533C, R533H,
534 5
535 4 R535X, R535G, R535Q,
536 0 D536H,
537 4
538 5 G538D,
539 7
540 8
541 8
542 9
543 10 F543L,
544 11
545 11
546 12
547 13
548 13
549 14
550 14
551 15 A551V, A551T,