SCN5A Variant A447G Detail

We estimate the penetrance of LQTS for SCN5A A447G around 4% and the Brugada syndrome penetrance around 7%. SCN5A A447G was found in a total of 20 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A447G is present in 19 alleles in gnomAD. A447G has been functionally characterized in 1 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 (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 A447G around 4% (0/30) and the Brugada syndrome penetrance around 7% (1/30).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.47 0.951 0.21 0.538 24 20
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: - 20 20 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.

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

A447G 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
432 15
433 14 R433S, R433C, R433H,
434 14
435 13
436 13
437 12 A437V,
438 11 M438T, M438L,
439 11 E439K, E439V,
440 10
441 9 L441F,
442 8
443 8
444 7 E444fsX14,
445 5 H445Q, H445D, H445Y,
446 4 E446K,
447 0 A447G, c.1339-24G>A, A447S, c.1338+2T>A,
448 4
449 5 Y449C, T449A,
450 7
451 8
452 8 G452D,
453 9 V453M,
454 10
455 11
456 11 V456M,
457 12
458 13 R458C, p.R458VfsX12, R458H,
459 13 S459G,
460 14
461 14 L461V,
462 15 E462K, E462A,