SCN5A Variant K343Q Detail

We estimate the penetrance of LQTS for SCN5A K343Q around 20% and the Brugada syndrome penetrance around 15%. SCN5A K343Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. K343Q is not present in gnomAD. K343Q has been functionally characterized in 1 papers. This residue is located in a Mild_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 (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 K343Q around 20% (1/10) and the Brugada syndrome penetrance around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.83 0.997 0.86 0.809 17 21
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)
18242854 2008 HEK 100 -1.74 -3.78 450

K343Q has 44 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
328 12
277 5
271 14 L271V,
326 13
276 9 L276P, L276Q,
348 13 P348A,
317 12 K317N, K317E, K317M,
270 15 Q270K,
279 8
385 13 A385T,
1552 14 Q1552R, Q1552L,
355 14 F355C, F355I,
1549 12
278 6 H278R, H278D,
356 11 D356N,
343 0
327 11
384 11 S384T,
354 12
340 12 R340Q, R340W,
1550 7
357 15
272 12
341 8 C341Y,
274 6 G274C,
273 9
325 12 L325R,
321 14 S321Y,
269 14
345 8
275 8 N275K,
280 12 C280Y,
323 13
347 11
351 14 G351D, G351S, G351V, G351C,
320 12 T320N,
342 6
1551 8 D1551N, D1551Y,
346 11 E346G, E346D, E346K, E346X,
344 5 A344S,
381 14 c.1141-3C>A, c.1140+1G>A,
380 15
281 11 V281M,
353 14 T353I,