SCN5A Variant L276Q Detail

We estimate the penetrance of LQTS for SCN5A L276Q around 6% and the Brugada syndrome penetrance around 64%. SCN5A L276Q was found in a total of 2 carriers in 5 papers and/or in gnomAD: 2 had Brugada syndrome, 0 had LQTS. L276Q is not present in gnomAD. L276Q has been functionally characterized in 6 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 L276Q around 6% (0/12) and the Brugada syndrome penetrance around 64% (7/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.85 1 -3.49 0.997 82 10
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
17697823 2007 1 0 1 0
23321620 2013 1 0 1 0
28341781 2017 1 0 1 0
20129283 2010 1 0 1 0
29325976 2018 2 0 2 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 0 2 -
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
17697823 2007
23321620 2013
28341781 2017
20129283 2010
32533946 2020 HEK 1
29325976 2018

L276Q has 73 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 13
333 14 c.998+1G>A, c.998+5G>A,
364 11
277 6
271 11 L271V,
326 11
276 0 L276P, L276Q,
363 14
348 7 P348A,
270 13 Q270K,
360 12
279 9
385 8 A385T,
355 7 F355I, F355C,
1549 14
278 7 H278R, H278D,
388 15 I388S,
356 9 D356N,
334 15 c.999-424_1338+81del,
361 11
904 14 W904X,
332 13 A332T,
343 9
365 14
327 11
376 11 R376H, R376C,
384 6 S384T,
354 6
329 14
386 11 G386E, G386R,
378 12
349 11 D349N,
267 14
379 12
1550 11
357 12
272 6
341 12 C341Y,
274 5 G274C,
273 9
325 7 L325R,
392 13
324 11
321 15 S321Y,
389 11 Y389X, Y389H,
269 11
345 11
393 12
275 5 N275K,
383 10
280 13 C280Y,
323 11
347 7
382 10
351 10 G351C, G351D, G351S, G351V,
265 14 A265V,
374 14 W374G,
350 13 H350Q,
342 12
367 13 R367H, R367L, R367C,
1551 14 D1551N, D1551Y,
346 11 E346K, E346X, E346G, E346D,
359 14 A359T, p.A359PfsX12,
344 10 A344S,
381 6 c.1141-3C>A, c.1140+1G>A,
322 13
375 15
352 12 Y352C,
368 14
380 7
268 10 G268S,
377 8
353 7 T353I,