SCN5A Variant E488Q Detail

We estimate the penetrance of LQTS for SCN5A E488Q around 2% and the Brugada syndrome penetrance around 6%. SCN5A E488Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E488Q is not present in gnomAD. E488Q has been functionally characterized in 0 papers. This residue is located in a Non_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 (0 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 E488Q around 2% (0/10) and the Brugada syndrome penetrance around 6% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.315 1 0
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 15 0 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.

E488Q 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
473 15 E473X,
474 14 R474G, R474K,
475 14 R475K, R475S,
476 13
477 13 c.1428_1431delCAAG,
478 12
479 11
480 11 K480N,
481 10 R481Q, R481W,
482 9 M482I,
483 8
484 8
485 7
486 5 T486S, T486A,
487 4
488 0
489 4
490 5 G490A, G490E,
491 7 E491G,
492 8
493 8 R493K,
494 9
495 10
496 11 K496N, K496M,
497 11 S497C,
498 12
499 13
500 13 E500K,
501 14 D501G,
502 14
503 15 P503S,