SCN5A Variant E375Q Detail

We estimate the penetrance of LQTS for SCN5A E375Q around 8% and the Brugada syndrome penetrance around 35%. SCN5A E375Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. E375Q is not present in gnomAD. E375Q 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 (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 E375Q around 8% (0/10) and the Brugada syndrome penetrance around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.943 47 7
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.

E375Q has 71 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 13
1702 11
901 12 E901K, S901L,
276 15 L276Q, L276P,
348 13 P348A,
1417 14
1715 9
1687 9
372 9
371 10 Q371E,
1711 5 c.5131delG,
904 15 W904X,
1707 10
1704 12 L1704H,
1706 6 Q1706H,
1716 9 p.L1716SfsX71,
1714 11 D1714G,
376 5 R376C, R376H,
1688 12
897 14 G897R, G897E,
1423 14 D1423H,
1692 10
386 15 G386E, G386R,
1422 14 M1422R,
1693 15
378 7
1699 14
1418 14
349 12 D349N,
373 6
1712 6 G1712C, G1712S,
379 6
1703 10
898 12
893 15 R893H, R893C,
397 13 I397V, I397T, I397F,
1719 14
1709 10 p.T1709del, T1709M, T1709R,
325 14 L325R,
1420 12 G1420D, G1420V, G1420R, G1420P,
900 12
324 14
393 11
1713 10
390 14
383 12
1708 12 T1708I,
382 11
1421 14
1718 14 S1718R,
374 6 W374G,
1705 11
1689 12 D1689N,
1700 15
1717 13 L1717P,
367 10 R367L, R367H, R367C,
370 13 T370M,
1752 14
381 11 c.1140+1G>A, c.1141-3C>A,
1686 11
375 0
1691 13
368 11
899 14
1710 9 S1710L,
380 9
377 7
1685 15
1419 9 K1419E,
353 13 T353I,
1414 14 Q1414H,