SCN5A Variant E346K Detail

We estimate the penetrance of LQTS for SCN5A E346K around 1% and the Brugada syndrome penetrance around 10%. SCN5A E346K was found in a total of 14 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E346K is present in 14 alleles in gnomAD. E346K has been functionally characterized in 1 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (2 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 E346K around 1% (0/24) and the Brugada syndrome penetrance around 10% (2/24).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.06 0.064 0.09 0.337 32 2
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
28837624 2017 1 0 0 1 AF
LITERATURE, COHORT, AND GNOMAD: - 14 14 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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)
28837624 2017

E346K has 43 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
277 7
276 11 L276Q, L276P,
348 8 P348A,
317 11 K317E, K317N, K317M,
360 12
279 9
355 14 F355C, F355I,
278 12 H278D, H278R,
356 11 D356N,
318 15
904 13 W904X,
343 11
871 15
354 10
349 10 D349N,
1550 12
357 14
274 11 G274C,
273 15
319 13 G319C, G319R, G319S,
325 12 L325R,
324 14
321 8 S321Y,
872 14 D872N,
345 4
275 14 N275K,
280 14 C280Y,
912 15 Q912R,
323 10
347 5
351 6 G351S, G351C, G351D, G351V,
320 10 T320N,
350 10 H350Q,
342 13
1551 14 D1551N, D1551Y,
346 0 E346D, E346K, E346X, E346G,
344 7 A344S,
322 9
352 9 Y352C,
380 14
908 13
281 13 V281M,
353 10 T353I,