SCN5A Variant S384F Detail

We estimate the penetrance of LQTS for SCN5A S384F around 7% and the Brugada syndrome penetrance around 20%. SCN5A S384F was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S384F is not present in gnomAD. S384F has been functionally characterized in 0 papers. This residue is located in a Mild_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 (1 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 S384F around 7% (0/10) and the Brugada syndrome penetrance around 20% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.939 21 5
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 14 0 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.

S384F has 64 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 7
333 8 c.998+1G>A, c.998+5G>A,
277 10
271 11 L271V,
1702 14
326 6
276 6 L276Q, L276P,
387 11
348 11 P348A,
279 10
385 4 A385T,
355 12 F355C, F355I,
330 11 S330F,
278 5 H278D, H278R,
388 11 I388S,
356 15 D356N,
334 9 c.999-424_1338+81del,
332 6 A332T,
343 11
327 5
376 13 R376C, R376H,
384 0 S384T,
354 12
329 8
1692 12
386 6 G386R, G386E,
340 14 R340W, R340Q,
378 11
1699 15
331 11
349 15 D349N,
379 10
1550 15
272 9
341 8 C341Y,
274 9 G274C,
273 13
335 11 C335S, C335R,
325 5 L325R,
1690 15 D1690N, c.5068_5070delGA,
392 13
324 10
389 9 Y389X, Y389H,
1620 15 T1620K, T1620M,
345 14
393 13
390 14
275 6 N275K,
383 6
280 10 C280Y,
323 12
347 12
382 7
1689 13 D1689N,
342 11
336 14 P336L,
344 12 A344S,
381 6 c.1141-3C>A, c.1140+1G>A,
1691 10
380 8
268 13 G268S,
377 11
281 14 V281M,
353 13 T353I,