SCN5A Variant T370K Detail

We estimate the penetrance of LQTS for SCN5A T370K around 16% and the Brugada syndrome penetrance around 23%. SCN5A T370K was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. T370K is not present in gnomAD. T370K 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 (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 T370K around 16% (0/10) and the Brugada syndrome penetrance around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.977 26 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 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.

T370K has 78 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
403 13
364 10
919 13
901 14 S901L, E901K,
363 10
896 12 C896S,
404 10 L404V, L404Q,
895 12 L895F,
1417 15
396 10 V396L, V396A,
894 11 I894M,
254 14
372 6
401 7 S401P,
926 13
1764 14 c.5290delG, V1764F,
371 5 Q371E,
409 14 L409P, L409V,
1711 12 c.5131delG,
928 9 L928P,
925 14 I925F,
361 14
904 14 W904X,
260 14
366 5
365 9
1706 14 Q1706H,
376 15 R376H, R376C,
258 14 V258A,
897 7 G897E, G897R,
924 11 V924I,
927 9 N927K, N927S,
369 5 M369K,
378 15
1418 13
902 14
402 10 F402L,
373 9
1768 15 I1768V,
898 10
893 13 R893C, R893H,
921 14
922 12 V922I,
399 14
397 9 I397V, I397F, I397T,
405 8
362 12
261 11
920 10
1709 11 T1709R, T1709M, p.T1709del,
900 10
392 15
393 13
916 14
264 14
929 14
1708 15 T1708I,
265 15 A265V,
408 12
374 9 W374G,
407 14
903 12 p.M903CfsX29,
367 7 R367L, R367H, R367C,
1760 14
370 0 T370M,
923 8
375 13
406 12 N406S, N406K,
368 7
899 7
1710 12 S1710L,
377 12
932 13
398 14
257 12
400 10 G400E, G400A, G400R,
1419 13 K1419E,
931 13