SCN5A Variant F366V Detail

We estimate the penetrance of LQTS for SCN5A F366V around 12% and the Brugada syndrome penetrance around 46%. SCN5A F366V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F366V is not present in gnomAD. F366V 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 (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A F366V around 12% (0/10) and the Brugada syndrome penetrance around 46% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.978 67 12
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 0 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.

F366V has 76 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
403 15
364 7
266 15 L266H,
919 12
363 6
404 10 L404Q, L404V,
360 12
396 10 V396A, V396L,
894 13 I894M,
355 13 F355C, F355I,
254 11
372 9
401 9 S401P,
926 14
371 10 Q371E,
250 15
928 11 L928P,
925 14 I925F,
361 10
904 13 W904X,
260 11
366 0
365 6
258 10 V258A,
354 14
897 11 G897R, G897E,
924 10 V924I,
927 12 N927S, N927K,
369 5 M369K,
902 14
402 14 F402L,
373 12
267 15
262 11 S262G,
898 13
256 13
921 12
922 12 V922I,
399 15
397 11 I397T, I397F, I397V,
405 11
261 7
362 6
920 7
900 10
392 14
255 14
918 14
393 14
917 12 L917R, L917V,
916 10
264 11
259 14
265 11 A265V,
408 13
253 14
374 12 W374G,
407 14
358 13
903 11 p.M903CfsX29,
367 7 R367C, R367H, R367L,
263 13 V263I,
359 11 p.A359PfsX12, A359T,
370 5 T370M,
923 9
352 15 Y352C,
406 14 N406K, N406S,
368 7
899 8
915 15 C915R,
268 14 G268S,
377 12
257 9
400 11 G400E, G400A, G400R,
353 13 T353I,
907 14