SCN5A Variant R523C Detail

We estimate the penetrance of LQTS for SCN5A R523C around 18% and the Brugada syndrome penetrance around 11%. SCN5A R523C was found in a total of 3 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. R523C is present in 2 alleles in gnomAD. R523C has been functionally characterized in 2 papers. This residue is located in a Non_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 R523C around 18% (1/13) and the Brugada syndrome penetrance around 11% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.12 0.996 -1.78 0.73 10 7
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
18752142 2008 1 1 0 0
18752973 2009 1 0 0 1 SUDEP
LITERATURE, COHORT, AND GNOMAD: - 3 2 1 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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
18752142 2008
18752973 2009

R523C 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
508 15
509 14
510 14
511 13
512 13 T512I,
513 12 c.1537delC, R513P, R513H, R513C,
514 11 G514C,
515 11
516 10
517 9 R517S,
518 8
519 8 S519F,
520 7 M520R, M520V,
521 5 c.1562delA, K521E,
522 4 P522S,
523 0 R523H, R523S, R523C,
524 4 S524Y, c.1570_1571insG,
525 5 S525G,
526 7 R526C, R526H,
527 8 G527R,
528 8 S528R,
529 9
530 10 F530V, F530S,
531 11 T531I, T531A,
532 11 F532C, F532L,
533 12 R533H, R533S, R533C,
534 13
535 13 R535G, R535X, R535Q,
536 14 D536H,
537 14
538 15 G538D,