SCN5A Variant V411E Detail

We estimate the penetrance of LQTS for SCN5A V411E around 47% and the Brugada syndrome penetrance around 16%. SCN5A V411E was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V411E is not present in gnomAD. V411E has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A V411E around 47% (2/10) and the Brugada syndrome penetrance around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.983 13 63
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 12 2 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.

V411E has 71 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
403 14
414 5 M414V,
939 13 L939F,
1643 12 I1643L,
404 11 L404V, L404Q,
937 15
1778 12
1773 13
249 6 K249X,
247 9 V247L,
254 11
1771 11 I1771T,
1777 13 V1777M, V1777L,
418 10 E418K,
926 14
250 6
409 7 L409P, L409V,
928 10 L928P,
925 14 I925F,
1650 13 L1650F,
417 11
933 10
246 6
935 12 L935P,
1779 10 T1779M,
412 4 V412D,
924 13 V924I,
1470 15
927 14 N927K, N927S,
245 9 Q245K,
1776 10
244 12
1769 14
415 6 A415T,
1649 13 A1649V,
1768 13 I1768V,
1774 13 c.5321_5324dupACTT, N1774D,
256 13
405 11
248 11
241 13
420 14
419 13 Q419X,
930 13 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
255 14
1772 9 L1772V,
1645 12 T1645M,
239 14 I239V , I239V,
251 10
410 4 A410V,
1780 13 E1780G,
242 10 A242D,
929 9
416 11 Y416C,
413 6 A413T, A413E,
408 6
253 8
407 6
936 11
1775 7 F1775V, p.F1775LfsX15,
1642 11 G1642E,
406 10 N406K, N406S,
252 11
411 0 V411M,
243 11
932 9
1647 13
257 13
931 14
1646 9
1782 14