SCN5A Variant c.703+1G>A Detail

We estimate the penetrance of LQTS for SCN5A c.703+1G>A around 25% and the Brugada syndrome penetrance around 20%. SCN5A c.703+1G>A was found in a total of 2 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. c.703+1G>A is not present in gnomAD. c.703+1G>A has been functionally characterized in 2 papers. This residue is located in a Mild_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 (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 c.703+1G>A around 25% (1/12) and the Brugada syndrome penetrance around 20% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 29 17
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
26669661 2016 2 1 0 0
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 2 1 1 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)
30059973 2018
26669661 2016

c.703+1G>A has 38 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
848 14 I848F,
937 13
839 12 L839P,
842 10
240 9 V240M,
231 9 c.692_693delCA,
193 15 W193X, W193R,
237 6
228 14 K228R,
836 12 V836M,
234 4 P234S,
229 13
933 14
845 11 c.2533delG,
232 9 V232I, V232F,
244 14
420 11
241 10
235 0 c.704-1G>C, G235R, c.703+1G>A,
840 10
843 13 T843A,
419 10 Q419X,
423 10
834 15 N834D,
837 8
239 7 I239V, I239V ,
230 10 I230V, I230M, I230T,
242 11 A242D,
416 12 Y416C,
841 6 p.N841TfsX2, N841K,
236 4
238 5
233 6
838 8
422 13
844 11 L844RfsX3,
243 13
835 12 S835A, S835L,