SCN5A Variant A359D Detail

We estimate the penetrance of LQTS for SCN5A A359D around 6% and the Brugada syndrome penetrance around 13%. SCN5A A359D was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A359D is not present in gnomAD. A359D 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 A359D around 6% (0/10) and the Brugada syndrome penetrance around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.858 9 3
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.

A359D has 56 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 9
277 15
266 11 L266H,
276 14 L276P, L276Q,
363 7
270 13 Q270K,
360 4
1552 15 Q1552L, Q1552R,
355 9 F355I, F355C,
1549 11
356 8 D356N,
1543 14 V1543L, V1543A,
1542 15
361 5
904 12 W904X,
366 11
365 10
258 13 V258A,
354 9
1546 10 M1546T,
1545 14
267 14
1550 13
262 11 S262G,
357 5
272 14
274 14 G274C,
362 6
911 14 G911E,
261 11
273 13
920 13
900 14
269 9
917 13 L917R, L917V,
913 13
916 10
264 14
912 10 Q912R,
347 13
1548 13 G1548K, E1548K,
351 12 G351S, G351C, G351D, G351V,
265 9 A265V,
358 5
903 13 p.M903CfsX29,
367 13 R367H, R367L, R367C,
263 14 V263I,
359 0 p.A359PfsX12, A359T,
1547 12 V1547L,
352 10 Y352C,
915 15 C915R,
368 14
899 15
268 11 G268S,
353 11 T353I,
907 12