SCN5A Variant V836G Detail

We estimate the penetrance of LQTS for SCN5A V836G around 10% and the Brugada syndrome penetrance around 18%. SCN5A V836G was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V836G is not present in gnomAD. V836G has been functionally characterized in 0 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 (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 V836G around 10% (0/10) and the Brugada syndrome penetrance around 18% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.979 18 10
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
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.

V836G has 33 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
937 11
839 6 L839P,
842 11
1455 13
836 0 V836M,
234 10 P234S,
934 13
845 14 c.2533delG,
830 11
833 5 G833R,
940 14 S940N,
831 10
938 13
235 12 c.703+1G>A, c.704-1G>C, G235R,
840 6
942 13
843 10 T843A,
1456 12
834 7 N834D,
1460 12 F1460L,
837 4
239 14 I239V, I239V ,
841 8 p.N841TfsX2, N841K,
236 15
941 11 S941F, S941N,
238 14
233 12
838 6
844 11 L844RfsX3,
829 11
832 7
835 4 S835L, S835A,
828 13 L828V,