SCN5A Variant F355L Detail

We estimate the penetrance of LQTS for SCN5A F355L around 29% and the Brugada syndrome penetrance around 47%. SCN5A F355L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F355L is not present in gnomAD. F355L 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 (4 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 F355L around 29% (1/10) and the Brugada syndrome penetrance around 47% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.856 68 37
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 10 1 4 - -
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.

F355L 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 6
277 10
271 8 L271V,
266 9 L266H,
276 7 L276P, L276Q,
363 9
348 11 P348A,
270 9 Q270K,
360 9
1627 15
396 12 V396A, V396L,
385 12 A385T,
1624 15 V1624I,
355 0 F355C, F355I,
1549 12
278 13 H278D, H278R,
372 15
356 7 D356N,
361 5
904 14 W904X,
366 13
343 14
365 8
376 14 R376C, R376H,
384 12 S384T,
354 5
386 14 G386E, G386R,
1546 12 M1546T,
369 14 M369K,
378 13
1545 14
349 13 D349N,
267 9
379 15
1550 11
262 12 S262G,
357 8
272 5
397 15 I397F, I397T, I397V,
274 8 G274C,
362 10
261 12
273 8
325 14 L325R,
900 14
392 9
389 11 Y389X, Y389H,
269 6
1620 14 T1620M, T1620K,
395 14
393 11
275 9 N275K,
264 10
347 10
382 13
1548 12 E1548K, G1548K,
351 11 G351S, G351C, G351V, G351D,
265 7 A265V,
374 14 W374G,
358 9
367 11 R367L, R367H, R367C,
1551 15 D1551Y, D1551N,
263 12 V263I,
346 14 E346X, E346D, E346G, E346K,
359 9 p.A359PfsX12, A359T,
1547 15 V1547L,
381 9 c.1140+1G>A, c.1141-3C>A,
368 10
352 12 Y352C,
380 11
268 5 G268S,
377 9
353 7 T353I,
1623 13 R1623X, R1623Q, R1623L, c.4867delC,