SCN5A Variant Q692K Detail

We estimate the penetrance of LQTS for SCN5A Q692K around 3% and the Brugada syndrome penetrance around 1%. SCN5A Q692K was found in a total of 96 carriers in 6 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. Q692K is present in 90 alleles in gnomAD. Q692K 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 (0 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 Q692K around 3% (3/106) and the Brugada syndrome penetrance around 1% (0/106).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-1.11 0 1.43 0.538 2 3
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
12566525 2003 1 1 0 0
17905336 2007 1 1 0 0
19322600 2009 1 0 0 1 SIDS
23631430 2013 1 1 0 0
27566755 2016 1 1 0 0
20129283 2010 3 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 96 93 3 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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)
25904541 2015 HEK 94 -2 -4 81
12566525 2003
17905336 2007
19322600 2009
23631430 2013
27566755 2016
20129283 2010

Q692K 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
677 15 E677V,
678 14
679 14
680 13 R680H, R680C,
681 13 H681P,
682 12
683 11 C683S, C683G, C683R,
684 11
685 10
686 9 C686F,
687 8
688 8
689 7 R689C, R689H,
690 5
691 4 A691T, A691S,
692 0 Q692K,
693 4 R693H, R693C,
694 5 Y694C,
695 7
696 8 I696N,
697 8
698 9 E698X,
699 10
700 11
701 11 P701L,
702 12
703 13
704 13 M704T,
705 14 S705F, S705P,
706 14
707 15