SCN5A Variant D349G Detail

We estimate the penetrance of LQTS for SCN5A D349G around 5% and the Brugada syndrome penetrance around 32%. SCN5A D349G was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. D349G is not present in gnomAD. D349G has been functionally characterized in 0 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 (3 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 D349G around 5% (0/10) and the Brugada syndrome penetrance around 32% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.937 43 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 12 0 3 - -
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.

D349G has 55 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 12
901 9 E901K, S901L,
276 11 L276Q, L276P,
363 13
348 4 P348A,
360 12
279 12
355 13 F355C, F355I,
278 15 H278R, H278D,
372 13
356 15 D356N,
361 15
904 7 W904X,
376 7 R376H, R376C,
384 15 S384T,
871 12
354 10
909 15
902 13
349 0 D349N,
373 11
379 12
898 15
274 15 G274C,
325 11 L325R,
900 10
324 10
321 12 S321Y,
872 11 D872N,
345 13
383 14
912 15 Q912R,
323 10
347 7
906 14
351 7 G351D, G351S, G351C, G351V,
374 15 W374G,
350 5 H350Q,
903 12 p.M903CfsX29,
367 11 R367L, R367H, R367C,
346 10 E346D, E346X, E346G, E346K,
344 14 A344S,
381 13 c.1141-3C>A, c.1140+1G>A,
322 9
905 10
375 12
352 9 Y352C,
899 14
380 8
377 10
908 11
873 15 S873A,
353 6 T353I,
907 12