SCN5A Variant W360R Detail

We estimate the penetrance of LQTS for SCN5A W360R around 7% and the Brugada syndrome penetrance around 20%. SCN5A W360R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. W360R is not present in gnomAD. W360R 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 W360R around 7% (0/10) and the Brugada syndrome penetrance around 20% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.968 22 4
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.

W360R has 59 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 8
277 12
266 14 L266H,
919 15
276 12 L276P, L276Q,
363 6
348 12 P348A,
360 0
355 9 F355I, F355C,
1549 12
356 7 D356N,
361 6
904 9 W904X,
366 12
365 11
354 7
1546 13 M1546T,
349 12 D349N,
1550 13
262 14 S262G,
357 6
272 14
274 13 G274C,
362 8
911 12 G911E,
261 14
273 13
920 13
900 12
269 11
345 15
917 13 L917R, L917V,
913 12
916 10
912 8 Q912R,
347 10
906 14
1548 15 E1548K, G1548K,
351 8 G351V, G351C, G351D, G351S,
910 15 S910L,
265 11 A265V,
350 11 H350Q,
358 9
903 10 p.M903CfsX29,
367 11 R367C, R367H, R367L,
346 12 E346X, E346G, E346D, E346K,
359 4 A359T, p.A359PfsX12,
1547 15 V1547L,
905 15
352 5 Y352C,
915 13 C915R,
368 14
899 13
268 12 G268S,
377 13
908 13
914 15
353 7 T353I,
907 9