SCN5A Variant L448H Detail

We estimate the penetrance of LQTS for SCN5A L448H around 11% and the Brugada syndrome penetrance around 22%. SCN5A L448H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L448H is not present in gnomAD. L448H has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_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 L448H around 11% (0/10) and the Brugada syndrome penetrance around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.598 28 12
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 13 0 2 - -
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.

L448H 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
433 15 R433C, R433S, R433H,
434 14
435 14
436 13
437 13 A437V,
438 12 M438T, M438L,
439 11 E439K, E439V,
440 11
441 10 L441F,
442 9
443 8
444 8 E444fsX14,
445 7 H445Q, H445Y, H445D,
446 5 E446K,
447 4 c.1339-24G>A, A447S, A447G, c.1338+2T>A,
448 0
449 4 T449A, Y449C,
450 5
451 7
452 8 G452D,
453 8 V453M,
454 9
455 10
456 11 V456M,
457 11
458 12 R458C, p.R458VfsX12, R458H,
459 13 S459G,
460 13
461 14 L461V,
462 14 E462K, E462A,
463 15 M463T, M463R,