SCN5A Variant Q380L Detail

We estimate the penetrance of LQTS for SCN5A Q380L around 20% and the Brugada syndrome penetrance around 38%. SCN5A Q380L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q380L is not present in gnomAD. Q380L 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 Q380L around 20% (0/10) and the Brugada syndrome penetrance around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.67 56 24
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.

Q380L has 78 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 15
333 11 c.998+5G>A, c.998+1G>A,
364 12
277 11
271 15 L271V,
1702 13
901 15 S901L, E901K,
326 10
276 7 L276Q, L276P,
363 15
387 14
348 7 P348A,
279 11
385 10 A385T,
355 11 F355C, F355I,
1687 12
278 10 H278R, H278D,
372 14
388 15 I388S,
356 15 D356N,
334 13 c.999-424_1338+81del,
1711 14 c.5131delG,
361 14
904 14 W904X,
332 12 A332T,
343 15
365 15
327 11
1706 12 Q1706H,
376 6 R376H, R376C,
384 8 S384T,
1688 14
354 10
329 14
1692 10
386 11 G386E, G386R,
378 8
349 8 D349N,
373 11
1712 14 G1712S, G1712C,
379 6
1703 14
272 11
341 14 C341Y,
274 12 G274C,
325 6 L325R,
900 14
392 14
324 8
321 15 S321Y,
389 12 Y389H, Y389X,
345 14
393 11
390 15
275 11 N275K,
383 7
280 12 C280Y,
323 10
347 10
382 8
351 12 G351D, G351V, G351C, G351S,
374 11 W374G,
1689 11 D1689N,
350 13 H350Q,
367 12 R367H, R367L, R367C,
346 14 E346K, E346X, E346G, E346D,
344 14 A344S,
381 5 c.1141-3C>A, c.1140+1G>A,
1686 14
322 12
375 9
1691 11
352 14 Y352C,
368 13
380 0
268 14 G268S,
377 6
353 8 T353I,