SCN5A Variant V240M Detail

We estimate the penetrance of LQTS for SCN5A V240M around 27% and the Brugada syndrome penetrance around 25%. SCN5A V240M was found in a total of 9 carriers in 6 papers and/or in gnomAD: 3 had Brugada syndrome, 2 had LQTS. V240M is present in 4 alleles in gnomAD. V240M has been functionally characterized in 6 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 (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A V240M around 27% (3/19) and the Brugada syndrome penetrance around 25% (4/19).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.93 1 0.05 0.917 20 49
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
24349418 2013 1 1 0 0
19843921 2009 1 0 1 0
21273195 2011 3 0 3 0
19716085 2009 1 1 0 0
20129283 2010 1 0 1 0
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 9 4 2 3 -
VARIANT FEATURES ALONE: - 15 13 1 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)
19843921 2009
21273195 2011
19716085 2009
20129283 2010
30059973 2018
24349418 2013 hiPSC-CM 81

V240M has 59 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 14
839 14 L839P,
842 10
249 14 K249X,
247 11 V247L,
240 0 V240M,
231 9 c.692_693delCA,
193 9 W193R, W193X,
418 13 E418K,
926 14
237 6
228 12 K228R,
925 12 I925F,
227 10 L227P,
234 12 P234S,
934 15
933 10
229 12
246 10
412 13 V412D,
196 14
852 15
245 9 Q245K,
845 8 c.2533delG,
232 12 V232F, V232I,
244 6
415 11 A415T,
191 14
849 11
226 14 A226G, A226V,
420 12
248 12
241 4
235 9 c.703+1G>A, c.704-1G>C, G235R,
840 13
843 13 T843A,
419 9 Q419X,
930 11 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
423 13
837 14
239 5 I239V, I239V ,
230 7 I230M, I230V, I230T,
242 6 A242D,
929 11
416 11 Y416C,
413 15 A413E, A413T,
841 10 p.N841TfsX2, N841K,
236 6
847 14
846 12 L846R,
192 12
936 14
238 7
233 9
838 12
422 14
844 12 L844RfsX3,
243 5