SCN5A Variant L382P Detail

We estimate the penetrance of LQTS for SCN5A L382P around 18% and the Brugada syndrome penetrance around 37%. SCN5A L382P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L382P is not present in gnomAD. L382P 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 L382P around 18% (0/10) and the Brugada syndrome penetrance around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.987 51 21
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.

L382P has 68 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
328 12
333 8 c.998+1G>A, c.998+5G>A,
271 12 L271V,
1702 7
326 11
276 10 L276Q, L276P,
387 7
348 14 P348A,
396 14 V396L, V396A,
385 6 A385T,
355 13 F355I, F355C,
1687 13
391 11
330 10 S330F,
278 12 H278D, H278R,
388 8 I388S,
1698 11 A1698T,
334 11 c.999-424_1338+81del,
1711 15 c.5131delG,
332 7 A332T,
1704 14 L1704H,
327 10
1706 11 Q1706H,
376 12 R376H, R376C,
384 7 S384T,
1688 14
354 14
329 9
1692 7
386 4 G386E, G386R,
1693 12
378 5
1699 10
331 9
379 7
1703 11
272 10
341 15 C341Y,
397 15 I397F, I397T, I397V,
274 14 G274C,
335 15 C335S, C335R,
1701 12 M1701I,
325 9 L325R,
1690 13 c.5068_5070delGA, D1690N,
392 10
324 12
1697 15
389 7 Y389X, Y389H,
395 15
393 8
394 12
390 8
275 11 N275K,
383 7
382 0
374 11 W374G,
1696 14
1705 11
1689 10 D1689N,
1700 13
381 4 c.1141-3C>A, c.1140+1G>A,
375 11
1691 7
368 14
380 8
268 14 G268S,
377 9
353 14 T353I,