SCN5A Variant L368P Detail

We estimate the penetrance of LQTS for SCN5A L368P around 16% and the Brugada syndrome penetrance around 45%. SCN5A L368P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L368P is not present in gnomAD. L368P 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 L368P around 16% (0/10) and the Brugada syndrome penetrance around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.986 66 17
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.

L368P has 77 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 13
364 6
271 14 L271V,
266 14 L266H,
276 14 L276Q, L276P,
363 9
404 12 L404Q, L404V,
360 14
396 5 V396L, V396A,
355 10 F355I, F355C,
391 13
372 8
401 8 S401P,
371 6 Q371E,
1711 12 c.5131delG,
928 15 L928P,
361 10
904 14 W904X,
260 12
366 7
365 5
1706 12 Q1706H,
376 12 R376C, R376H,
258 14 V258A,
354 13
897 13 G897E, G897R,
369 6 M369K,
378 10
402 11 F402L,
373 9
267 12
1712 15 G1712C, G1712S,
379 13
262 13 S262G,
898 14
399 11
272 12
397 6 I397V, I397T, I397F,
405 12
362 10
261 10
920 14
1709 10 T1709M, p.T1709del, T1709R,
900 11
392 8
389 14 Y389H, Y389X,
269 14
395 10
393 7
390 13
394 11
264 9
1708 14 T1708I,
382 14
265 10 A265V,
374 6 W374G,
1705 12
358 14
903 15 p.M903CfsX29,
367 5 R367C, R367L, R367H,
263 13 V263I,
359 14 p.A359PfsX12, A359T,
370 7 T370M,
381 11 c.1140+1G>A, c.1141-3C>A,
923 14
375 11
406 15 N406K, N406S,
368 0
899 11
380 13
1710 13 S1710L,
268 11 G268S,
377 7
398 12
257 13
400 9 G400R, G400E, G400A,
353 12 T353I,