SCN5A Variant R34C Detail

We estimate the penetrance of LQTS for SCN5A R34C around 0% and the Brugada syndrome penetrance around 0%. SCN5A R34C was found in a total of 2977 carriers in 7 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. R34C is present in 2928 alleles in gnomAD. R34C has been functionally characterized in 12 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 R34C around 0% (3/2987) and the Brugada syndrome penetrance around 0% (0/2987).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.7 0.984 -2.76 None 0 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
11960580 2001 2 0 0 0
19322600 2009 9 0 0 9 SIDS
21964171 2011 1 0 0 1 SUDS
23714088 2013 2 2 0 0
24687331 2014 1 1 0 0
23571586 2013 1 0 0 1 stillbirth, SUDS
20129283 2010 44 0 0 0
LITERATURE, COHORT, AND GNOMAD: - 2977 2974 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)
11997281 2002
15851227 2004
15898185 2004
19322600 2009
21964171 2011
23714088 2013
24687331 2014
23571586 2013
15992733 2005
15992732 2005 HEK 83 -2 0
20129283 2010
11960580 2001

R34C 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
19 15
20 14 S20F,
21 14 L21V,
22 13 A22V,
23 13 A23S,
24 12
25 11 E25K,
26 11
27 10 R27C, R27L, R27H,
28 9 M28T, M28L, M28I,
29 8 A29V, A29E,
30 8 E30G,
31 7
32 5
33 4
34 0 R34H, R34C,
35 4 G35S,
36 5
37 7 T37A,
38 8
39 8 L39F,
40 9
41 10
42 11
43 11 R43Q, R43X,
44 12
45 13 G45A,
46 13
47 14
48 14 E48K,
49 15 E49K,