SCN5A Variant R689H Detail

We estimate the penetrance of LQTS for SCN5A R689H around 7% and the Brugada syndrome penetrance around 11%. SCN5A R689H was found in a total of 30 carriers in 10 papers and/or in gnomAD: 3 had Brugada syndrome, 2 had LQTS. R689H is present in 23 alleles in gnomAD. R689H has been functionally characterized in 10 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Mild_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 R689H around 7% (2/40) and the Brugada syndrome penetrance around 11% (4/40).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.11 0.004 -0.55 0.582 5 11
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
22490985 2012 1 0 1 0
23692053 2013 1 0 0 1 SUDS
15996170 2005 1 0 0 1 VT, Mitral Valve Disease
16414944 2005 1 1 0 0
20541041 2010 1 1 0 0
21321465 2011 1 0 1 0
28341781 2017 1 0 1 0
16453024 2006 1 0 0 1 SIDS
26746457 2016 1 0 0 0
20129283 2010 1 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 30 25 2 3 -
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)
22490985 2012 HEK 0
23692053 2013 HEK 83 -0.7 -0.6 200
15996170 2005
16414944 2005
20541041 2010
21321465 2011
28341781 2017
16453024 2006
26746457 2016
20129283 2010

R689H 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
674 15
675 14 c.2024_2025delAG,
676 14
677 13 E677V,
678 13
679 12
680 11 R680H, R680C,
681 11 H681P,
682 10
683 9 C683G, C683R, C683S,
684 8
685 8
686 7 C686F,
687 5
688 4
689 0 R689C, R689H,
690 4
691 5 A691T, A691S,
692 7 Q692K,
693 8 R693C, R693H,
694 8 Y694C,
695 9
696 10 I696N,
697 11
698 11 E698X,
699 12
700 13
701 13 P701L,
702 14
703 14
704 15 M704T,