SCN5A Variant H445D Detail

We estimate the penetrance of LQTS for SCN5A H445D around 0% and the Brugada syndrome penetrance around 9%. SCN5A H445D was found in a total of 15 carriers in 4 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. H445D is present in 14 alleles in gnomAD. H445D has been functionally characterized in 4 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 H445D around 0% (0/25) and the Brugada syndrome penetrance around 9% (2/25).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.37 0.011 -1.22 0.63 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
18378609 2008 2 0 0 2 AF
22818067 2012 3 0 0 3 AF
25650408 2015 1 0 1 0
28086167 2017 1 0 0 1 MI
LITERATURE, COHORT, AND GNOMAD: - 15 14 0 1 -
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.

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)
18378609 2008
22818067 2012
25650408 2015
28086167 2017

H445D 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 R433H, R433C, R433S,
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 H445D, H445Y, H445Q,
446 4 E446K,
447 5 c.1338+2T>A, A447G, A447S, c.1339-24G>A,
448 7
449 8 Y449C, T449A,
450 8
451 9
452 10 G452D,
453 11 V453M,
454 11
455 12
456 13 V456M,
457 13
458 14 p.R458VfsX12, R458C, R458H,
459 14 S459G,
460 15