SCN5A Variant L363I Detail

We estimate the penetrance of LQTS for SCN5A L363I around 11% and the Brugada syndrome penetrance around 35%. SCN5A L363I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L363I is not present in gnomAD. L363I 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 (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L363I around 11% (0/10) and the Brugada syndrome penetrance around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.839 49 10
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.

L363I has 78 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 4
266 14 L266H,
901 13 E901K, S901L,
919 12
276 14 L276Q, L276P,
363 0
348 13 P348A,
360 6
396 13 V396L, V396A,
894 14 I894M,
355 9 F355I, F355C,
372 10
401 15 S401P,
356 12 D356N,
371 14 Q371E,
361 6
904 8 W904X,
366 6
260 15
365 7
376 14 R376C, R376H,
258 13 V258A,
354 9
897 14 G897E, G897R,
924 15 V924I,
1546 15 M1546T,
369 11 M369K,
911 14 G911E,
902 13
349 13 D349N,
373 12
267 15
262 12 S262G,
357 10
898 15
921 14
922 15 V922I,
272 14
397 15 I397F, I397V, I397T,
362 5
261 10
920 9
900 8
392 15
269 13
918 13
393 15
917 11 L917R, L917V,
913 13
916 8
264 13
912 11 Q912R,
347 13
906 13
351 11 G351D, G351C, G351S, G351V,
265 10 A265V,
374 14 W374G,
350 12 H350Q,
358 10
903 8 p.M903CfsX29,
367 6 R367H, R367L, R367C,
263 15 V263I,
359 7 A359T, p.A359PfsX12,
370 10 T370M,
923 12
905 14
352 9 Y352C,
915 12 C915R,
368 9
899 8
380 15
268 12 G268S,
377 11
908 15
914 15
257 14
353 8 T353I,
907 10