SCN5A Variant T449A Detail

We estimate the penetrance of LQTS for SCN5A T449A around 2% and the Brugada syndrome penetrance around 21%. SCN5A T449A was found in a total of 3 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T449A is present in 2 alleles in gnomAD. T449A has been functionally characterized in 1 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 (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 T449A around 2% (0/13) and the Brugada syndrome penetrance around 21% (2/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
0.84 0 -1 0.262 40 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
20129283 2010 1 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 3 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.

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)
20129283 2010

T449A 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
434 15
435 14
436 14
437 13 A437V,
438 13 M438L, M438T,
439 12 E439K, E439V,
440 11
441 11 L441F,
442 10
443 9
444 8 E444fsX14,
445 8 H445Y, H445D, H445Q,
446 7 E446K,
447 5 c.1339-24G>A, c.1338+2T>A, A447G, A447S,
448 4
449 0 T449A, Y449C,
450 4
451 5
452 7 G452D,
453 8 V453M,
454 8
455 9
456 10 V456M,
457 11
458 11 R458C, p.R458VfsX12, R458H,
459 12 S459G,
460 13
461 13 L461V,
462 14 E462A, E462K,
463 14 M463T, M463R,
464 15