SCN5A Variant E462A Detail

We estimate the penetrance of LQTS for SCN5A E462A around 40% and the Brugada syndrome penetrance around 9%. SCN5A E462A was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. E462A is not present in gnomAD. E462A has been functionally characterized in 2 papers. This residue is located in a Non_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 (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 E462A around 40% (2/11) and the Brugada syndrome penetrance around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.27 0.779 -0.57 0.771 0 35
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
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 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.

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)
19716085 2009
25904541 2015 HEK 91 -3 1 95

E462A 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
447 15 A447G, c.1339-24G>A, A447S, c.1338+2T>A,
448 14
449 14 Y449C, T449A,
450 13
451 13
452 12 G452D,
453 11 V453M,
454 11
455 10
456 9 V456M,
457 8
458 8 R458C, p.R458VfsX12, R458H,
459 7 S459G,
460 5
461 4 L461V,
462 0 E462K, E462A,
463 4 M463T, M463R,
464 5
465 7 p.P465LfsX5,
466 8 L466F,
467 8
468 9 P468L,
469 10 V469I,
470 11 N470K,
471 11
472 12
473 13 E473X,
474 13 R474G, R474K,
475 14 R475K, R475S,
476 14
477 15 c.1428_1431delCAAG,