SCN5A Variant R878H Detail

We estimate the penetrance of LQTS for SCN5A R878H around 3% and the Brugada syndrome penetrance around 73%. SCN5A R878H was found in a total of 5 carriers in 5 papers and/or in gnomAD: 5 had Brugada syndrome, 0 had LQTS. R878H is not present in gnomAD. R878H has been functionally characterized in 6 papers. This residue is located in a 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 (5 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 R878H around 3% (0/15) and the Brugada syndrome penetrance around 73% (10/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.85 1 2.44 0.967 93 0
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
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 5 0 0 5 -
VARIANT FEATURES ALONE: - 15 10 0 5 - -
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)
25904541 2015 HEK 0
20129283 2010
20129283 2010
20129283 2010
20129283 2010
20129283 2010

R878H has 55 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
880 9
888 15
890 11 I890T,
901 9 E901K, S901L,
1430 10 D1430N,
1426 5
894 15 I894M,
1447 14
1444 12 L1444I,
1440 7 W1440X,
1380 14 p.N1380del, N1380K,
1429 10
1442 15 Y1442N, Y1442C,
1450 15
887 13
886 9 H886Q, H886P,
1362 13 c.4083delG, R1362S,
1438 14 P1438L,
871 13
1423 7 D1423H,
876 9
1431 14 S1431C,
1422 7 M1422R,
902 11
882 14
892 15 F892I,
881 13
898 12
893 10 R893C, R893H,
889 10
1420 11 G1420R, G1420V, G1420P, G1420D,
900 14
1360 15 F1360C,
872 13 D872N,
1425 9
865 13
1427 10 A1427S, A1427E,
1424 11 I1424V,
1439 13 Q1439H, Q1439R,
906 14
874 12 G874D,
878 0 R878H, R878C, R878L,
1421 11
885 14
350 15 H350Q,
1441 11 E1441Q,
877 6
879 4 W879R,
883 14
905 11
875 12
1428 12 A1428S, A1428V,
908 15
873 14 S873A,
1419 15 K1419E,