SCN5A Variant S524Y Detail

We estimate the penetrance of LQTS for SCN5A S524Y around 0% and the Brugada syndrome penetrance around 0%. SCN5A S524Y was found in a total of 1169 carriers in 3 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. S524Y is present in 1150 alleles in gnomAD. S524Y has been functionally characterized in 8 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 S524Y around 0% (0/1179) and the Brugada syndrome penetrance around 0% (2/1179).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.55 0.959 -1.03 None 29 2
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
16453024 2006 3 0 0 2 SIDS
23571586 2013 1 0 0 1 stillbirth, SUDS
20129283 2010 18 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 1169 1169 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.

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)
17331104 2007 HEK 113 -5 1.6
15851227 2004
15898185 2004
15992732 2005 HEK 84 -1 -2
16453024 2006
23571586 2013
15992733 2005
20129283 2010

S524Y 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
509 15
510 14
511 14
512 13 T512I,
513 13 R513C, c.1537delC, R513P, R513H,
514 12 G514C,
515 11
516 11
517 10 R517S,
518 9
519 8 S519F,
520 8 M520V, M520R,
521 7 c.1562delA, K521E,
522 5 P522S,
523 4 R523H, R523S, R523C,
524 0 c.1570_1571insG, S524Y,
525 4 S525G,
526 5 R526C, R526H,
527 7 G527R,
528 8 S528R,
529 8
530 9 F530S, F530V,
531 10 T531I, T531A,
532 11 F532C, F532L,
533 11 R533C, R533H, R533S,
534 12
535 13 R535Q, R535X, R535G,
536 13 D536H,
537 14
538 14 G538D,
539 15