SCN5A Variant E417Q Detail

We estimate the penetrance of LQTS for SCN5A E417Q around 12% and the Brugada syndrome penetrance around 17%. SCN5A E417Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E417Q is not present in gnomAD. E417Q has been functionally characterized in 0 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 E417Q around 12% (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 0.797 17 12
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.

E417Q has 51 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 7 M414V,
939 9 L939F,
937 10
1778 15
1773 13
842 15
249 13 K249X,
943 11 S943N,
1777 14 V1777M, V1777L,
418 6 E418K,
409 12 L409V, L409P,
417 0
934 14
933 11
1471 13
246 12
935 12 L935P,
1779 12 T1779M,
412 10 V412D,
1470 13
245 12 Q245K,
1776 10
415 7 A415T,
940 7 S940N,
420 5
938 12
1474 14
241 12
942 13
419 7 Q419X,
423 10
1772 12 L1772V,
239 12 I239V , I239V,
410 11 A410V,
1780 11 E1780G,
242 10 A242D,
416 5 Y416C,
413 6 A413E, A413T,
941 11 S941N, S941F,
1783 14
936 8
238 10
838 14
422 9
1467 14
1775 13 F1775V, p.F1775LfsX15,
421 5
411 11 V411M,
243 14
932 14
1489 13 E1489D,