SCN5A Variant N347D Detail

We estimate the penetrance of LQTS for SCN5A N347D around 5% and the Brugada syndrome penetrance around 26%. SCN5A N347D was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. N347D is not present in gnomAD. N347D 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 N347D around 5% (0/10) and the Brugada syndrome penetrance around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.925 32 2
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.

N347D has 60 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 6
326 14
276 7 L276P, L276Q,
363 13
348 4 P348A,
317 15 K317N, K317M, K317E,
360 10
279 9
355 10 F355C, F355I,
1549 14
278 10 H278D, H278R,
356 9 D356N,
361 12
904 10 W904X,
343 11
376 12 R376C, R376H,
384 12 S384T,
354 6
349 7 D349N,
1550 11
357 12
272 13
341 15 C341Y,
274 9 G274C,
273 13
325 10 L325R,
900 14
324 12
321 11 S321Y,
269 14
872 15 D872N,
345 7
275 11 N275K,
383 14
280 14 C280Y,
912 14 Q912R,
323 10
347 0
351 4 G351S, G351C, G351V, G351D,
320 13 T320N,
350 8 H350Q,
903 15 p.M903CfsX29,
342 13
367 14 R367L, R367H, R367C,
1551 15 D1551Y, D1551N,
346 5 E346X, E346D, E346G, E346K,
359 13 p.A359PfsX12, A359T,
344 9 A344S,
381 12 c.1140+1G>A, c.1141-3C>A,
322 9
905 15
352 7 Y352C,
380 10
268 15 G268S,
377 11
908 13
281 15 V281M,
353 5 T353I,
907 14