SCN5A Variant R451W Detail

We estimate the penetrance of LQTS for SCN5A R451W around 6% and the Brugada syndrome penetrance around 17%. SCN5A R451W was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R451W is not present in gnomAD. R451W has been functionally characterized in 0 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 R451W around 6% (0/10) and the Brugada syndrome penetrance around 17% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.61 18 5
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 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.

R451W 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
436 15
437 14 A437V,
438 14 M438L, M438T,
439 13 E439V, E439K,
440 13
441 12 L441F,
442 11
443 11
444 10 E444fsX14,
445 9 H445Q, H445Y, H445D,
446 8 E446K,
447 8 A447G, A447S, c.1338+2T>A, c.1339-24G>A,
448 7
449 5 Y449C, T449A,
450 4
451 0
452 4 G452D,
453 5 V453M,
454 7
455 8
456 8 V456M,
457 9
458 10 p.R458VfsX12, R458H, R458C,
459 11 S459G,
460 11
461 12 L461V,
462 13 E462A, E462K,
463 13 M463R, M463T,
464 14
465 14 p.P465LfsX5,
466 15 L466F,