SCN5A Variant N406S Detail

We estimate the penetrance of LQTS for SCN5A N406S around 42% and the Brugada syndrome penetrance around 22%. SCN5A N406S was found in a total of 2 carriers in 3 papers and/or in gnomAD: 1 had Brugada syndrome, 1 had LQTS. N406S is not present in gnomAD. N406S has been functionally characterized in 5 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A N406S around 42% (2/12) and the Brugada syndrome penetrance around 22% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.91 0.999 0.5 0.94 20 50
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
15877619 2005 1 0 1 0
24667783 2015 1 1 0 0
28341781 2017 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 1 1 -
VARIANT FEATURES ALONE: - 15 13 1 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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
17761312 2007
24667783 2015
28341781 2017
17445919 2007 HEK 95 15.9 10
15877619 2005 HEK 95 15.9 9.6 0

N406S has 77 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 7
414 13 M414V,
939 14 L939F,
404 7 L404V, L404Q,
1773 11
1765 9
396 14 V396L, V396A,
1653 11
254 14
1771 6 I1771T,
401 7 S401P,
1652 14 M1652R, M1652T,
1764 10 V1764F, c.5290delG,
371 11 Q371E,
250 12
409 5 L409P, L409V,
928 10 L928P,
1650 10 L1650F,
260 14
366 14
1656 14
933 14
246 14
935 10 L935P,
412 10 V412D,
924 14 V924I,
1762 15 p.I1762del, I1762M,
1470 11
927 12 N927S, N927K,
1466 10 c.4396_4397insG,
1776 13
369 10 M369K,
1767 8 Y1767C,
1660 13 I1660S, I1660V,
1654 13
1769 8
402 7 F402L,
1766 12 M1766T, M1766V, M1766L,
415 15 A415T,
1649 12 A1649V,
1768 5 I1768V,
1774 12 c.5321_5324dupACTT, N1774D,
1473 14 F1473C, F1473S,
256 13
399 12
397 12 I397F, I397T, I397V,
405 4
1657 11
1709 14 T1709R, p.T1709del, T1709M,
930 15 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1772 7 L1772V,
410 7 A410V,
1770 9 I1770V,
929 13
413 11 A413E, A413T,
408 7
253 12
407 6
936 13
1763 13 V1763M, V1763L,
1760 14
1467 13
1775 10 p.F1775LfsX15, F1775V,
370 12 T370M,
923 15
1469 13 I1469V,
406 0 N406S, N406K,
368 15
411 10 V411M,
932 9
398 11
1647 14
257 12
400 9 G400R, G400A, G400E,
931 13
1646 12
1463 13 N1463Y,