SCN5A Variant E418Q Detail

We estimate the penetrance of LQTS for SCN5A E418Q around 7% and the Brugada syndrome penetrance around 11%. SCN5A E418Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E418Q is not present in gnomAD. E418Q 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 (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 E418Q around 7% (0/10) and the Brugada syndrome penetrance around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.733 6 6
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.

E418Q has 42 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
414 6 M414V,
939 14 L939F,
937 14
1778 14
249 9 K249X,
247 14 V247L,
240 13 V240M,
1777 15 V1777M, V1777L,
418 0 E418K,
250 14
409 14 L409V, L409P,
237 13
417 6
933 13
246 10
1779 10 T1779M,
412 10 V412D,
245 8 Q245K,
1776 12
244 12
415 5 A415T,
940 13 S940N,
420 8
248 13
241 10
419 5 Q419X,
423 9
239 12 I239V , I239V,
410 12 A410V,
1780 10 E1780G,
242 9 A242D,
416 8 Y416C,
413 9 A413T, A413E,
1783 11
936 12
238 11
422 7
1775 13 p.F1775LfsX15, F1775V,
421 7
411 10 V411M,
243 12
1782 13