SCN5A Variant F392Y Detail

We estimate the penetrance of LQTS for SCN5A F392Y around 16% and the Brugada syndrome penetrance around 29%. SCN5A F392Y was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F392Y is not present in gnomAD. F392Y has been functionally characterized in 0 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 (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 F392Y around 16% (0/10) and the Brugada syndrome penetrance around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.919 37 18
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 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.

F392Y has 68 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 8 L271V,
1702 13
266 11 L266H,
276 13 L276Q, L276P,
363 15
387 13
362 14
270 12 Q270K,
1627 12
396 6 V396L, V396A,
385 11 A385T,
1624 11 V1624I,
355 9 F355I, F355C,
391 6
401 13 S401P,
388 10 I388S,
371 13 Q371E,
361 12
260 13
366 14
365 9
1706 14 Q1706H,
384 13 S384T,
354 13
386 11 G386E, G386R,
369 12 M369K,
378 10
402 14 F402L,
267 7
379 14
1625 15
262 13 S262G,
399 10
272 8
397 9 I397V, I397F, I397T,
274 15 G274C,
261 12
273 14
1628 14
392 0
389 7 Y389X, Y389H,
269 11
1620 12 T1620K, T1620M,
395 6
393 4
390 8
394 7
275 13 N275K,
264 7
382 10
265 9 A265V,
374 11 W374G,
1705 12
358 15
367 13 R367L, R367C, R367H,
263 11 V263I,
370 15 T370M,
381 9 c.1141-3C>A, c.1140+1G>A,
368 8
380 14
268 7 G268S,
377 10
398 12
400 11 G400A, G400R, G400E,
1621 13
353 15 T353I,
1623 13 R1623X, R1623L, c.4867delC, R1623Q,