SCN5A Variant L377H Detail

We estimate the penetrance of LQTS for SCN5A L377H around 9% and the Brugada syndrome penetrance around 29%. SCN5A L377H was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L377H is not present in gnomAD. L377H 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 (2 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 L377H around 9% (0/10) and the Brugada syndrome penetrance around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.99 37 7
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 13 0 2 - -
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.

L377H has 80 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
277 14
271 14 L271V,
1702 13
901 13 S901L, E901K,
276 8 L276Q, L276P,
363 11
348 9 P348A,
360 13
396 11 V396L, V396A,
385 12 A385T,
355 9 F355C, F355I,
1687 14
391 15
278 14 H278R, H278D,
372 9
401 15 S401P,
356 14 D356N,
371 11 Q371E,
1711 11 c.5131delG,
361 11
904 12 W904X,
366 12
365 10
1706 10 Q1706H,
376 6 R376C, R376H,
384 11 S384T,
354 9
1692 13
386 12 G386E, G386R,
369 13 M369K,
378 7
349 10 D349N,
373 8
267 15
1712 13 G1712C, G1712S,
379 7
1703 14
898 14
272 10
397 11 I397F, I397T, I397V,
274 13 G274C,
362 14
1709 13 T1709R, T1709M, p.T1709del,
325 11 L325R,
900 10
392 10
324 13
389 12 Y389H, Y389X,
269 14
395 15
393 8
394 14
390 13
275 12 N275K,
264 14
383 11
347 11
382 9
351 12 G351C, G351S, G351D, G351V,
265 13 A265V,
374 6 W374G,
1705 13
1689 15 D1689N,
350 13 H350Q,
903 14 p.M903CfsX29,
367 6 R367L, R367C, R367H,
370 12 T370M,
381 6 c.1141-3C>A, c.1140+1G>A,
375 7
1691 14
352 13 Y352C,
368 7
899 12
1710 15 S1710L,
380 6
268 12 G268S,
377 0
1419 15 K1419E,
353 7 T353I,