SCN5A Variant H445P Detail

We estimate the penetrance of LQTS for SCN5A H445P around 6% and the Brugada syndrome penetrance around 14%. SCN5A H445P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. H445P is not present in gnomAD. H445P 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 (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 H445P around 6% (0/10) and the Brugada syndrome penetrance around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.645 12 4
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.

H445P 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
430 15 K430E,
431 14
432 14
433 13 R433C, R433S, R433H,
434 13
435 12
436 11
437 11 A437V,
438 10 M438L, M438T,
439 9 E439K, E439V,
440 8
441 8 L441F,
442 7
443 5
444 4 E444fsX14,
445 0 H445Y, H445Q, H445D,
446 4 E446K,
447 5 A447G, c.1338+2T>A, A447S, c.1339-24G>A,
448 7
449 8 T449A, Y449C,
450 8
451 9
452 10 G452D,
453 11 V453M,
454 11
455 12
456 13 V456M,
457 13
458 14 R458H, R458C, p.R458VfsX12,
459 14 S459G,
460 15