SCN5A Variant M369K Detail

We estimate the penetrance of LQTS for SCN5A M369K around 9% and the Brugada syndrome penetrance around 62%. SCN5A M369K was found in a total of 3 carriers in 6 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. M369K is not present in gnomAD. M369K has been functionally characterized in 7 papers. This residue is located in a 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 (5 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 M369K around 9% (0/13) and the Brugada syndrome penetrance around 62% (8/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.89 0.963 -3.37 0.986 71 18
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
12106943 2002 1 0 1 0
16643399 2006 1 0 1 0
17404158 2007 1 0 1 0
26921764 2016 3 0 3 0
20129283 2010 1 0 1 0
30059973 2018 3 3 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 0 0 3 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
30059973 2018
12106943 2002
16643399 2006
17404158 2007
26921764 2016
20129283 2010
32533946 2020 HEK 3

M369K has 65 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 10
364 9
363 11
404 6 L404V, L404Q,
396 7 V396L, V396A,
355 14 F355C, F355I,
254 11
372 10
1771 14 I1771T,
401 4 S401P,
1764 15 c.5290delG, V1764F,
371 7 Q371E,
250 14
409 14 L409V, L409P,
928 10 L928P,
1650 15 L1650F,
361 12
260 9
366 5
365 6
258 11 V258A,
897 12 G897E, G897R,
924 12 V924I,
927 12 N927S, N927K,
369 0 M369K,
1767 14 Y1767C,
402 9 F402L,
373 13
1768 14 I1768V,
267 14
262 12 S262G,
256 11
399 10
397 7 I397T, I397F, I397V,
405 7
362 10
261 7
920 12
1709 12 T1709M, p.T1709del, T1709R,
900 14
392 12
255 14
395 11
393 11
394 13
264 9
259 13
265 11 A265V,
408 11
374 11 W374G,
253 12
407 11
367 9 R367L, R367H, R367C,
263 12 V263I,
370 5 T370M,
923 11
406 10 N406S, N406K,
368 6
899 11
268 14 G268S,
377 13
932 14
398 11
257 8
400 5 G400A, G400E, G400R,