SCN5A Variant R893C Detail

We estimate the penetrance of LQTS for SCN5A R893C around 2% and the Brugada syndrome penetrance around 42%. SCN5A R893C was found in a total of 6 carriers in 5 papers and/or in gnomAD: 3 had Brugada syndrome, 0 had LQTS. R893C is present in 3 alleles in gnomAD. R893C has been functionally characterized in 5 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 (3 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 R893C around 2% (0/16) and the Brugada syndrome penetrance around 42% (6/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.69 1 -5.8 0.967 49 1
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
28341781 2017 1 0 1 0
20129283 2010 2 0 2 0
29574140 2018 1 0 1 0
30059973 2018 1 1 0 0
30371189 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 6 3 0 3 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
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)
29574140 2018
30059973 2018
30371189 2018
28341781 2017
20129283 2010

R893C has 69 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
891 8 I891N, I891T,
880 12
888 10
890 6 I890T,
901 7 E901K, S901L,
919 10
896 7 C896S,
895 8 L895F,
1417 13
1426 13
894 5 I894M,
1447 13
372 9
926 13
1429 15
371 14 Q371E,
1711 15 c.5131delG,
1450 13
904 13 W904X,
887 11
1451 13 V1451L, V1451D,
886 11 H886P, H886Q,
1458 14 S1458Y,
376 15 R376C, R376H,
897 6 G897E, G897R,
1423 11 D1423H,
927 12 N927S, N927K,
854 13 c.2559delT,
1422 6 M1422R,
857 15 G857D,
1418 8
902 7
892 7 F892I,
373 10
881 12
898 4
893 0 R893C, R893H,
922 11 V922I,
920 14
889 7
1420 10 G1420D, G1420R, G1420V, G1420P,
900 9
1459 14 c.4376_4379delTCTT,
918 14
1425 10
1454 12
1424 13 I1424V,
906 13
878 10 R878L, R878H, R878C,
1421 7
885 15
903 11 p.M903CfsX29,
367 13 R367L, R367H, R367C,
1416 13 A1416E, c.4245+2T>A, c.4245+1G>C, c.4245+1G>A, A1416G,
853 13
370 13 T370M,
877 12
879 7 W879R,
923 10
905 11
375 15
915 14 C915R,
899 8
1710 15 S1710L,
1415 11
850 13 V850M, c.2549_2550insTG,
1419 10 K1419E,
1414 14 Q1414H,
931 14