SCN5A Variant W565C Detail

We estimate the penetrance of LQTS for SCN5A W565C around 6% and the Brugada syndrome penetrance around 14%. SCN5A W565C was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. W565C is not present in gnomAD. W565C 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 W565C around 6% (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 0.602 14 5
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.

W565C has 31 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
550 15
551 14 A551V, A551T,
552 14 G552W, G552R,
553 13 E553K, E553X,
554 13 S554I, S554N,
555 12 E555K,
556 11
557 11 H557Y, H557Q, H557L,
558 10 H558R,
559 9 T559R, T559I,
560 8
561 8
562 7
563 5 V563G,
564 4
565 0
566 4
567 5 L567Q,
568 7 R568H, R568C,
569 8 R569Q, R569W, c.1705dupC,
570 8 T570N,
571 9 S571I,
572 10 A572D, A572F, A572V, A572S,
573 11 Q573R, Q573E, Q573X,
574 11 G574E, c.1721delG,
575 12
576 13
577 13 S577N,
578 14 P578T, P578R,
579 14 G579R,
580 15