SCN5A Variant Y378C Detail

We estimate the penetrance of LQTS for SCN5A Y378C around 12% and the Brugada syndrome penetrance around 32%. SCN5A Y378C was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Y378C is not present in gnomAD. Y378C 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 Y378C around 12% (0/10) and the Brugada syndrome penetrance around 32% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.926 43 12
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.

Y378C 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
333 13 c.998+1G>A, c.998+5G>A,
364 13
271 14 L271V,
1702 6
326 15
276 12 L276P, L276Q,
387 10
348 14 P348A,
396 11 V396A, V396L,
385 10 A385T,
355 13 F355I, F355C,
1715 14
1687 12
391 11
372 13
388 11 I388S,
1698 12 A1698T,
401 15 S401P,
371 12 Q371E,
1711 10 c.5131delG,
332 12 A332T,
1707 11
1694 15
365 13
1704 11 L1704H,
327 15
1706 6 Q1706H,
1716 13 p.L1716SfsX71,
376 9 R376H, R376C,
1688 13
384 11 S384T,
354 15
329 14
1668 13 M1668T,
1692 8
386 9 G386E, G386R,
1693 13
378 0
1699 11
331 13
373 11
1712 11 G1712S, G1712C,
379 5
1703 8
272 12
397 10 I397F, I397T, I397V,
1709 11 T1709M, p.T1709del, T1709R,
1701 11 M1701I,
325 12 L325R,
392 10
324 14
389 9 Y389X, Y389H,
395 13
393 6
1713 14
390 8
394 10
275 14 N275K,
383 10
1708 12 T1708I,
382 5
374 6 W374G,
1705 7
1689 12 D1689N,
1700 12
367 12 R367H, R367C, R367L,
370 15 T370M,
381 6 c.1140+1G>A, c.1141-3C>A,
375 7
1691 10
368 10
1710 13 S1710L,
380 8
268 14 G268S,
377 7
398 14
353 14 T353I,