SCN5A Variant A344E Detail

We estimate the penetrance of LQTS for SCN5A A344E around 8% and the Brugada syndrome penetrance around 14%. SCN5A A344E was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A344E is not present in gnomAD. A344E 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 (1 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 A344E around 8% (0/10) and the Brugada syndrome penetrance around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.693 13 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 1 - -
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.

A344E has 44 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
328 15
277 5
326 12
276 10 L276P, L276Q,
348 10 P348A,
317 8 K317M, K317N, K317E,
279 5
1549 15
278 7 H278R, H278D,
356 12 D356N,
318 13
343 5
327 12
339 14
384 12 S384T,
354 12
282 14 R282H, R282C,
340 12 R340Q, R340W,
349 14 D349N,
283 14
1550 10
341 9 C341Y,
274 9 G274C,
273 13
319 11 G319S, G319C, G319R,
325 10 L325R,
324 13
321 9 S321Y,
345 3
275 10 N275K,
280 10 C280Y,
323 10
347 9
351 12 G351C, G351V, G351S, G351D,
320 8 T320N,
342 6
1551 11 D1551N, D1551Y,
346 7 E346G, E346X, E346D, E346K,
344 0 A344S,
322 11
352 15 Y352C,
380 14
281 8 V281M,
353 13 T353I,