SCN5A Variant F532C Detail

We estimate the penetrance of LQTS for SCN5A F532C around 20% and the Brugada syndrome penetrance around 24%. SCN5A F532C was found in a total of 12 carriers in 7 papers and/or in gnomAD: 4 had Brugada syndrome, 3 had LQTS. F532C is present in 4 alleles in gnomAD. F532C has been functionally characterized in 7 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 F532C around 20% (3/22) and the Brugada syndrome penetrance around 24% (5/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.75 0.999 0.15 0.89 9 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
18596570 2008 1 0 0 1 SIDS
15996170 2005 1 0 0 1 AF, AT, MS
20541041 2010 3 3 0 0
28341781 2017 1 0 1 0
29062695 2017 2 0 2 0
26746457 2016 1 0 0 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 12 5 3 4 -
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)
18596570 2008 tsA201 100 0 0
15996170 2005
20541041 2010
28341781 2017
29062695 2017
26746457 2016
20129283 2010

F532C 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
517 15 R517S,
518 14
519 14 S519F,
520 13 M520V, M520R,
521 13 c.1562delA, K521E,
522 12 P522S,
523 11 R523C, R523H, R523S,
524 11 S524Y, c.1570_1571insG,
525 10 S525G,
526 9 R526C, R526H,
527 8 G527R,
528 8 S528R,
529 7
530 5 F530V, F530S,
531 4 T531A, T531I,
532 0 F532C, F532L,
533 4 R533C, R533H, R533S,
534 5
535 7 R535G, R535X, R535Q,
536 8 D536H,
537 8
538 9 G538D,
539 10
540 11
541 11
542 12
543 13 F543L,
544 13
545 14
546 14
547 15