SCN5A Variant F362L Detail

We estimate the penetrance of LQTS for SCN5A F362L around 9% and the Brugada syndrome penetrance around 30%. SCN5A F362L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. F362L is not present in gnomAD. F362L 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 (3 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 F362L around 9% (0/10) and the Brugada syndrome penetrance around 30% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.895 40 8
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 12 0 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.

F362L has 62 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 7
266 10 L266H,
919 15
363 5
404 14 L404Q, L404V,
270 14 Q270K,
360 8
396 12 V396A, V396L,
355 10 F355C, F355I,
254 12
372 14
401 14 S401P,
356 12 D356N,
1543 14 V1543A, V1543L,
1542 14
361 5
904 14 W904X,
260 10
366 6
365 6
258 8 V258A,
354 12
924 15 V924I,
1546 10 M1546T,
369 10 M369K,
267 12
262 7 S262G,
357 10
256 14
921 15
272 14
397 15 I397F, I397T, I397V,
362 0
261 6
920 10
900 13
392 14
255 13
269 11
917 12 L917R, L917V,
916 10
264 10
912 14 Q912R,
259 12
265 6 A265V,
358 6
903 13 p.M903CfsX29,
367 10 R367L, R367H, R367C,
263 10 V263I,
359 6 p.A359PfsX12, A359T,
1547 15 V1547L,
370 12 T370M,
923 14
352 13 Y352C,
368 10
899 12
268 11 G268S,
377 14
257 10
400 14 G400R, G400E, G400A,
353 13 T353I,
907 14