SCN5A Variant p.N841TfsX2 Detail

We estimate the penetrance of LQTS for SCN5A p.N841TfsX2 around 63% and the Brugada syndrome penetrance around 12%. SCN5A p.N841TfsX2 was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. p.N841TfsX2 is not present in gnomAD. p.N841TfsX2 has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A p.N841TfsX2 around 63% (3/11) and the Brugada syndrome penetrance around 12% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 11 75
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
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 12 2 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)
30059973 2018

p.N841TfsX2 has 48 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 11 I848F,
937 10
839 7 L839P,
842 6
240 10 V240M,
231 11 c.692_693delCA,
1455 14
237 11
227 14 L227P,
836 8 V836M,
234 6 P234S,
934 11
933 11
229 11
845 7 c.2533delG,
232 10 V232F, V232I,
833 13 G833R,
940 14 S940N,
849 13
420 13
938 14
241 12
235 6 c.704-1G>C, c.703+1G>A, G235R,
840 4
843 7 T843A,
419 13 Q419X,
930 12 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
423 14
834 13 N834D,
837 5
239 7 I239V , I239V,
230 9 I230V, I230M, I230T,
242 12 A242D,
416 12 Y416C,
841 0 p.N841TfsX2, N841K,
236 7
847 11
941 14 S941F, S941N,
846 10 L846R,
936 14
238 8
233 5
838 5
844 6 L844RfsX3,
243 12
832 14
835 9 S835L, S835A,
931 15