SCN5A Variant T353I Detail

We estimate the penetrance of LQTS for SCN5A T353I around 9% and the Brugada syndrome penetrance around 68%. SCN5A T353I was found in a total of 5 carriers in 1 papers and/or in gnomAD: 5 had Brugada syndrome, 0 had LQTS. T353I is not present in gnomAD. T353I has been functionally characterized in 4 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 (5 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 T353I around 9% (0/15) and the Brugada syndrome penetrance around 68% (10/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.86 0.98 1.78 0.973 82 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
17198989 2007 5 0 5 0
LITERATURE, COHORT, AND GNOMAD: - 5 0 0 5 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
17198989 2007 HEK 24 1 11 5333
17198990 2007
32533946 2020 HEK 0
25261036 2015 HEK 58 2.2 -6.32 574

T353I has 70 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 7
277 9
271 15 L271V,
901 12 S901L, E901K,
276 7 L276P, L276Q,
363 8
348 5 P348A,
360 7
279 13
385 15 A385T,
355 7 F355C, F355I,
278 13 H278R, H278D,
372 12
356 9 D356N,
361 9
904 8 W904X,
366 13
343 14
365 11
376 9 R376H, R376C,
384 13 S384T,
354 4
378 14
902 14
349 6 D349N,
373 12
379 13
1550 14
357 11
272 11
274 10 G274C,
362 13
273 13
325 11 L325R,
900 10
392 15
324 13
269 13
345 12
393 14
916 14
275 12 N275K,
383 14
912 13 Q912R,
323 13
347 5
382 14
351 5 G351C, G351S, G351V, G351D,
265 13 A265V,
374 13 W374G,
350 8 H350Q,
358 14
903 11 p.M903CfsX29,
367 9 R367C, R367L, R367H,
346 10 E346K, E346D, E346X, E346G,
359 11 p.A359PfsX12, A359T,
344 13 A344S,
381 10 c.1140+1G>A, c.1141-3C>A,
322 13
905 13
375 13
352 6 Y352C,
368 12
899 13
380 8
268 12 G268S,
377 7
908 13
353 0 T353I,
907 12