SCN5A Variant I239V Detail

We estimate the penetrance of LQTS for SCN5A I239V around 76% and the Brugada syndrome penetrance around 8%. SCN5A I239V was found in a total of 3 carriers in 5 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. I239V is not present in gnomAD. I239V has been functionally characterized in 5 papers. This residue is located in a Non_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 (3 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A I239V around 76% (6/13) and the Brugada syndrome penetrance around 8% (1/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 6 83
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
15176425 2004 5 5 0 0
20566482 2010 2 0 2 0
20659946 2010 4 4 0 0
23098067 2012 1 1 0 0
30036649 2018 3 3 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 0 -
VARIANT FEATURES ALONE: - 15 11 3 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)
20566482 2010
20659946 2010
23098067 2012
30036649 2018
15176425 2004

I239V has 66 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
414 14 M414V,
848 12 I848F,
939 15 L939F,
937 9
839 10 L839P,
842 6
249 15 K249X,
247 13 V247L,
240 5 V240M,
231 12 c.692_693delCA,
193 14 W193X, W193R,
418 12 E418K,
926 13
237 8
925 13 I925F,
227 13 L227P,
836 14 V836M,
234 10 P234S,
417 12
934 11
933 7
229 13
246 10
935 13 L935P,
412 11 V412D,
245 11 Q245K,
845 7 c.2533delG,
232 13 V232F, V232I,
244 9
415 10 A415T,
940 13 S940N,
849 12
420 10
248 14
938 14
241 6
235 7 c.704-1G>C, c.703+1G>A, G235R,
840 9
843 10 T843A,
419 8 Q419X,
930 9 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
423 12
837 10
239 0 I239V , I239V,
230 9 I230V, I230M, I230T,
242 5 A242D,
929 10
416 7 Y416C,
413 12 A413T, A413E,
841 7 p.N841TfsX2, N841K,
236 6
847 13
941 14 S941F, S941N,
846 10 L846R,
936 10
238 4
233 9
838 8
422 13
421 14
844 10 L844RfsX3,
411 14 V411M,
243 6
932 13
835 13 S835L, S835A,
931 12