SCN5A Variant Q435R Detail

We estimate the penetrance of LQTS for SCN5A Q435R around 3% and the Brugada syndrome penetrance around 15%. SCN5A Q435R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q435R is not present in gnomAD. Q435R 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 Q435R around 3% (0/10) and the Brugada syndrome penetrance around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.339 17 2
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.

Q435R 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
420 15
421 14
422 14
423 13
424 13 I424M,
425 12 A425T, A425P,
426 11
427 11
428 10 E428K,
429 9 p.E429del, E429K,
430 8 K430E,
431 8
432 7
433 5 R433S, R433C, R433H,
434 4
435 0
436 4
437 5 A437V,
438 7 M438L, M438T,
439 8 E439K, E439V,
440 8
441 9 L441F,
442 10
443 11
444 11 E444fsX14,
445 12 H445D, H445Y, H445Q,
446 13 E446K,
447 13 A447G, c.1338+2T>A, c.1339-24G>A, A447S,
448 14
449 14 Y449C, T449A,
450 15