SCN5A Variant S401K Detail

We estimate the penetrance of LQTS for SCN5A S401K around 35% and the Brugada syndrome penetrance around 13%. SCN5A S401K was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S401K is not present in gnomAD. S401K has been functionally characterized in 1 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 S401K around 35% (1/10) and the Brugada syndrome penetrance around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.92 0.999 -2.88 None 10 49
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 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)
17205354 2007 HEK 85 0 7

S401K 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 7
364 13
363 15
404 6 L404Q, L404V,
1765 13
396 7 V396A, V396L,
1653 15
254 13
372 11
1771 11 I1771T,
401 0 S401P,
1764 10 c.5290delG, V1764F,
371 6 Q371E,
409 12 L409P, L409V,
1711 14 c.5131delG,
928 11 L928P,
1650 13 L1650F,
260 10
366 9
365 10
1706 15 Q1706H,
258 14 V258A,
897 13 G897E, G897R,
924 14 V924I,
927 13 N927S, N927K,
369 4 M369K,
1767 9 Y1767C,
1660 14 I1660V, I1660S,
378 15
1654 14
1769 14
402 4 F402L,
373 14
1768 10 I1768V,
262 15 S262G,
256 13
399 8
397 5 I397V, I397F, I397T,
405 5
1657 12
362 14
1759 15 S1759C,
261 10
1709 10 T1709R, p.T1709del, T1709M,
392 13
1772 14 L1772V,
395 11
393 11
394 11
410 14 A410V,
1770 14 I1770V,
264 11
1658 15
1708 12 T1708I,
259 15
265 15 A265V,
408 10
374 11 W374G,
253 13
1705 14
407 10
367 12 R367H, R367C, R367L,
1763 14 V1763L, V1763M,
263 14 V263I,
1760 14
370 7 T370M,
1661 14 G1661R, G1661E,
923 13
406 7 N406S, N406K,
368 8
899 14
1710 13 S1710L,
377 15
932 13
398 8
257 10
400 4 G400E, G400R, G400A,
1664 14