SCN5A Variant I408L Detail

We estimate the penetrance of LQTS for SCN5A I408L around 51% and the Brugada syndrome penetrance around 14%. SCN5A I408L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. I408L is not present in gnomAD. I408L has been functionally characterized in 0 papers. This residue is located in a Non_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 I408L around 51% (2/10) and the Brugada syndrome penetrance around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.908 10 69
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.

I408L has 78 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 11
414 10 M414V,
1643 13 I1643L,
404 6 L404V, L404Q,
895 15 L895F,
1773 15
1765 15
249 10 K249X,
247 10 V247L,
254 8
1771 10 I1771T,
401 10 S401P,
926 11
371 14 Q371E,
250 6
409 5 L409P, L409V,
928 6 L928P,
925 12 I925F,
1650 12 L1650F,
260 13
366 13
934 15
933 11
258 14 V258A,
246 8
935 11 L935P,
1779 14 T1779M,
412 7 V412D,
897 15 G897E, G897R,
924 9 V924I,
927 9 N927S, N927K,
1466 14 c.4396_4397insG,
245 13 Q245K,
1776 14
369 11 M369K,
1767 14 Y1767C,
244 15
1769 14
402 12 F402L,
415 11 A415T,
1649 14 A1649V,
1768 11 I1768V,
1774 15 c.5321_5324dupACTT, N1774D,
256 11
921 14
922 15 V922I,
405 5
248 13
261 14
920 14
930 11 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
255 13
1772 10 L1772V,
251 11
410 6 A410V,
242 13 A242D,
1770 15 I1770V,
929 8
416 14 Y416C,
413 9 A413E, A413T,
408 0
253 7
407 5
936 12
1775 10 p.F1775LfsX15, F1775V,
370 12 T370M,
1642 14 G1642E,
923 12
406 7 N406S, N406K,
252 12
411 6 V411M,
243 12
932 7
1647 14
257 9
400 11 G400R, G400A, G400E,
931 11
1646 11