SCN5A Variant D1423H Detail

We estimate the penetrance of LQTS for SCN5A D1423H around 4% and the Brugada syndrome penetrance around 21%. SCN5A D1423H was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D1423H is present in 1 alleles in gnomAD. D1423H has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 D1423H around 4% (0/11) and the Brugada syndrome penetrance around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.99 1 -2.89 0.918 24 2
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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

D1423H has 63 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
890 15 I890T,
901 12 E901K, S901L,
1417 14
1430 11 D1430N,
1426 6
1715 11
1361 14
1444 15 L1444I,
1440 12 W1440X,
1397 14 c.4189delT, c.4190delA,
1380 14 p.N1380del, N1380K,
1429 11
1711 15 c.5131delG,
1450 12
1398 9 V1398M,
1411 11
886 15 H886Q, H886P,
1410 15
1716 15 p.L1716SfsX71,
1714 9 D1714G,
376 15 R376H, R376C,
1362 11 c.4083delG, R1362S,
1438 14 P1438L,
1423 0 D1423H,
1378 14 V1378M,
1431 13 S1431C,
1422 5 M1422R,
1418 12
902 15
373 14
1712 12 G1712S, G1712C,
1359 15 K1359M, K1359N,
1356 14 c.4066_4068delTT,
898 12
893 11 R893H, R893C,
1412 14 L1412F,
1408 15 G1408R,
889 13
1420 5 G1420V, G1420R, G1420P, G1420D,
1360 10 F1360C,
1401 12
1425 7
1399 11
1713 15
1427 7 A1427S, A1427E,
1424 5 I1424V,
1364 15 I1364V,
878 7 R878C, R878H, R878L,
1400 9 V1400I,
1718 12 S1718R,
1421 8
1717 14 L1717P,
1416 14 A1416G, A1416E, c.4245+1G>C, c.4245+1G>A, c.4245+2T>A,
877 13
879 9 W879R,
1686 13
375 14
1415 11
1428 9 A1428V, A1428S,
1419 10 K1419E,
1414 10 Q1414H,
1402 13
1413 15