SCN5A Variant C373S Detail

We estimate the penetrance of LQTS for SCN5A C373S around 16% and the Brugada syndrome penetrance around 37%. SCN5A C373S was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. C373S is not present in gnomAD. C373S 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 C373S around 16% (0/10) and the Brugada syndrome penetrance around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.668 54 19
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.

C373S has 67 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 11
901 8 S901L, E901K,
919 14
363 12
896 12 C896S,
348 13 P348A,
895 15 L895F,
1417 13
396 14 V396A, V396L,
894 12 I894M,
1715 13
1687 14
372 4
401 14 S401P,
371 8 Q371E,
1711 8 c.5131delG,
904 11 W904X,
366 12
1707 13
365 13
1706 10 Q1706H,
1716 14 p.L1716SfsX71,
1714 13 D1714G,
376 7 R376H, R376C,
354 15
897 8 G897E, G897R,
1423 14 D1423H,
927 15 N927K, N927S,
369 13 M369K,
1422 12 M1422R,
378 11
1418 11
902 11
349 11 D349N,
373 0
1712 9 G1712C, G1712S,
379 11
898 7
893 10 R893C, R893H,
397 13 I397V, I397T, I397F,
920 15
1709 10 p.T1709del, T1709M, T1709R,
1420 11 G1420D, G1420V, G1420P, G1420R,
900 7
393 13
1713 12
1708 14 T1708I,
1421 11
374 7 W374G,
1705 15
350 13 H350Q,
903 12 p.M903CfsX29,
367 6 R367H, R367L, R367C,
370 9 T370M,
879 15 W879R,
381 14 c.1141-3C>A, c.1140+1G>A,
923 13
905 14
375 6
368 9
899 8
1710 10 S1710L,
380 11
377 8
1419 8 K1419E,
353 12 T353I,
1414 14 Q1414H,