SCN5A Variant P348T Detail

We estimate the penetrance of LQTS for SCN5A P348T around 5% and the Brugada syndrome penetrance around 22%. SCN5A P348T was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. P348T is not present in gnomAD. P348T 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 P348T around 5% (0/10) and the Brugada syndrome penetrance around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.948 25 1
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.

P348T has 61 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 12
277 8
901 13 S901L, E901K,
326 13
276 7 L276P, L276Q,
363 13
348 0 P348A,
360 12
279 8
385 14 A385T,
355 11 F355I, F355C,
278 11 H278D, H278R,
356 12 D356N,
361 14
904 10 W904X,
343 13
327 14
376 8 R376H, R376C,
384 11 S384T,
354 7
378 14
349 4 D349N,
373 13
379 12
1550 15
357 14
272 13
341 15 C341Y,
274 11 G274C,
273 15
325 8 L325R,
900 12
324 9
321 11 S321Y,
872 13 D872N,
345 9
275 12 N275K,
383 11
280 12 C280Y,
323 8
347 4
382 14
351 6 G351D, G351V, G351C, G351S,
320 14 T320N,
350 7 H350Q,
903 15 p.M903CfsX29,
342 14
367 13 R367H, R367C, R367L,
346 8 E346X, E346K, E346G, E346D,
344 10 A344S,
381 11 c.1140+1G>A, c.1141-3C>A,
322 8
905 14
375 13
352 9 Y352C,
380 7
377 9
908 13
281 15 V281M,
353 5 T353I,
907 15