SCN5A Variant Q379L Detail

We estimate the penetrance of LQTS for SCN5A Q379L around 16% and the Brugada syndrome penetrance around 36%. SCN5A Q379L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q379L is not present in gnomAD. Q379L 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 Q379L around 16% (0/10) and the Brugada syndrome penetrance around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.927 50 18
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.

Q379L 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 11 c.998+5G>A, c.998+1G>A,
364 15
1702 9
326 12
276 12 L276P, L276Q,
387 12
348 12 P348A,
385 12 A385T,
355 15 F355I, F355C,
1715 11
1687 7
278 15 H278R, H278D,
372 14
388 14 I388S,
1698 13 A1698T,
334 13 c.999-424_1338+81del,
371 15 Q371E,
1711 10 c.5131delG,
332 11 A332T,
1707 12
1694 14
1704 13 L1704H,
327 13
1706 7 Q1706H,
1716 11 p.L1716SfsX71,
376 6 R376H, R376C,
1714 14 D1714G,
384 10 S384T,
1688 10
1684 13 W1684R,
354 15
329 15
1692 6
386 10 G386R, G386E,
1693 11
378 5
1699 11
331 14
349 12 D349N,
373 11
1712 10 G1712C, G1712S,
379 0
1703 9
272 14
397 15 I397V, I397T, I397F,
1719 14
1709 13 p.T1709del, T1709M, T1709R,
1701 14 M1701I,
325 9 L325R,
1690 12 c.5068_5070delGA, D1690N,
392 14
324 10
389 13 Y389X, Y389H,
393 11
1713 14
390 12
275 15 N275K,
383 7
1708 15 T1708I,
323 14
382 7
374 9 W374G,
1705 11
1689 7 D1689N,
1700 13
367 13 R367L, R367C, R367H,
381 7 c.1141-3C>A, c.1140+1G>A,
1686 11
375 6
1691 8
368 13
1710 14 S1710L,
380 6
377 7
1685 14
1419 14 K1419E,
353 13 T353I,