SCN5A Variant F393I Detail

We estimate the penetrance of LQTS for SCN5A F393I around 20% and the Brugada syndrome penetrance around 33%. SCN5A F393I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F393I is not present in gnomAD. F393I has been functionally characterized in 0 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 (3 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 F393I around 20% (1/10) and the Brugada syndrome penetrance around 33% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.978 44 23
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 11 1 3 - -
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.

F393I has 74 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
364 11
271 11 L271V,
1702 10
266 15 L266H,
276 12 L276Q, L276P,
363 15
387 11
396 6 V396A, V396L,
385 11 A385T,
1624 15 V1624I,
355 11 F355C, F355I,
391 7
372 13
401 11 S401P,
388 10 I388S,
1698 14 A1698T,
371 10 Q371E,
1711 13 c.5131delG,
361 13
332 15 A332T,
366 14
1707 14
365 9
1704 14 L1704H,
1706 10 Q1706H,
376 13 R376H, R376C,
384 13 S384T,
354 14
1668 15 M1668T,
1692 13
386 10 G386E, G386R,
369 11 M369K,
378 6
1699 15
402 12 F402L,
373 13
267 11
379 11
1703 13
399 11
272 10
397 7 I397F, I397V, I397T,
261 14
1709 11 T1709M, p.T1709del, T1709R,
1701 13 M1701I,
392 4
389 8 Y389H, Y389X,
269 14
395 8
393 0
390 7
394 6
275 14 N275K,
383 14
264 10
1708 13 T1708I,
382 8
265 12 A265V,
374 7 W374G,
1705 8
367 11 R367L, R367H, R367C,
263 14 V263I,
370 13 T370M,
381 8 c.1140+1G>A, c.1141-3C>A,
375 11
1691 15
368 7
380 11
1710 15 S1710L,
268 10 G268S,
377 8
398 11
400 11 G400A, G400E, G400R,
353 14 T353I,