SCN5A Variant W374C Detail

We estimate the penetrance of LQTS for SCN5A W374C around 8% and the Brugada syndrome penetrance around 51%. SCN5A W374C was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. W374C is not present in gnomAD. W374C has been functionally characterized in 0 papers. This residue is located in a 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 (5 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 W374C around 8% (0/10) and the Brugada syndrome penetrance around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.935 77 6
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 10 0 5 - -
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.

W374C has 76 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 10
1702 11
901 15 S901L, E901K,
276 14 L276P, L276Q,
363 14
1417 14
396 10 V396A, V396L,
355 14 F355C, F355I,
1715 14
1687 14
391 14
372 8
401 11 S401P,
1764 14 c.5290delG, V1764F,
371 6 Q371E,
1711 6 c.5131delG,
361 15
366 12
1707 10
365 11
1704 12 L1704H,
1706 6 Q1706H,
1716 13 p.L1716SfsX71,
1714 15 D1714G,
376 9 R376C, R376H,
897 12 G897R, G897E,
1668 15 M1668T,
1692 12
386 14 G386E, G386R,
369 11 M369K,
378 6
1418 14
402 12 F402L,
349 15 D349N,
373 7
1712 9 G1712S, G1712C,
379 9
1703 11
898 12
399 14
272 15
397 7 I397F, I397T, I397V,
405 15
1759 14 S1759C,
1709 7 T1709R, p.T1709del, T1709M,
1701 14 M1701I,
900 12
392 11
1755 15
389 14 Y389X, Y389H,
395 13
393 7
1713 12
390 12
394 11
383 15
264 14
1708 10 T1708I,
382 11
374 0 W374G,
1705 9
367 8 R367L, R367H, R367C,
1760 13
370 9 T370M,
381 10 c.1140+1G>A, c.1141-3C>A,
375 6
368 6
899 12
1710 9 S1710L,
380 11
377 6
398 13
400 13 G400R, G400E, G400A,
1419 11 K1419E,
353 13 T353I,
1664 15