SCN5A Variant L365P Detail

We estimate the penetrance of LQTS for SCN5A L365P around 13% and the Brugada syndrome penetrance around 44%. SCN5A L365P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L365P is not present in gnomAD. L365P 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 L365P around 13% (0/10) and the Brugada syndrome penetrance around 44% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.979 63 13
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.

L365P has 72 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 5
271 13 L271V,
266 10 L266H,
276 14 L276P, L276Q,
363 7
404 12 L404Q, L404V,
270 14 Q270K,
360 11
1627 15
396 7 V396A, V396L,
355 8 F355C, F355I,
391 15
254 14
372 11
401 10 S401P,
356 13 D356N,
371 11 Q371E,
361 6
904 14 W904X,
260 9
366 6
365 0
258 11 V258A,
354 11
1546 13 M1546T,
369 6 M369K,
378 13
402 14 F402L,
373 13
267 9
262 9 S262G,
357 12
256 14
399 12
272 11
397 9 I397F, I397V, I397T,
405 14
362 6
261 6
273 15
920 13
900 12
392 9
389 14 Y389X, Y389H,
269 11
395 11
393 9
916 14
394 13
264 7
259 12
265 6 A265V,
374 11 W374G,
358 10
903 14 p.M903CfsX29,
367 7 R367H, R367C, R367L,
263 9 V263I,
359 10 A359T, p.A359PfsX12,
370 9 T370M,
381 13 c.1141-3C>A, c.1140+1G>A,
923 14
368 5
899 12
352 15 Y352C,
380 15
268 8 G268S,
377 10
398 14
257 11
400 10 G400E, G400R, G400A,
353 11 T353I,