SCN5A Variant W879R Detail

We estimate the penetrance of LQTS for SCN5A W879R around 11% and the Brugada syndrome penetrance around 68%. SCN5A W879R was found in a total of 2 carriers in 2 papers and/or in gnomAD: 2 had Brugada syndrome, 0 had LQTS. W879R is not present in gnomAD. W879R has been functionally characterized in 3 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 (6 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 W879R around 11% (0/12) and the Brugada syndrome penetrance around 68% (8/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-13.52 0.998 -2.56 0.903 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
29325976 2018 1 0 1 0
29759671 2018 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 0 2 -
VARIANT FEATURES ALONE: - 15 9 0 6 - -
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)
32533946 2020 HEK 0
29325976 2018
29759671 2018

W879R 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
891 11 I891T, I891N,
880 7
888 11
890 7 I890T,
901 8 E901K, S901L,
919 14
862 14
896 13 C896S,
895 14 L895F,
1430 12 D1430N,
1426 8
894 11 I894M,
1447 11
1444 10 L1444I,
1440 9 W1440X,
1429 10
1450 13
904 14 W904X,
887 9
1451 14 V1451L, V1451D,
886 6 H886P, H886Q,
871 15
897 14 G897R, G897E,
909 15
1423 9 D1423H,
854 14 c.2559delT,
876 10
1422 6 M1422R,
857 14 G857D,
1418 14
902 8
882 12
892 11 F892I,
373 15
881 10
898 10
893 7 R893C, R893H,
889 7
1420 12 G1420R, G1420P, G1420V, G1420D,
900 13
858 14 M858L,
1425 8
865 11
1427 12 A1427E, A1427S,
1424 12 I1424V,
1448 15 I1448T, I1448L,
884 13
906 12
874 15 G874D,
878 4 R878C, R878L, R878H,
1421 10
885 11
1443 15 N1443S,
903 14 p.M903CfsX29,
1441 12 E1441Q,
877 6
879 0 W879R,
883 11
905 10
899 14
875 13
1415 14
1428 12 A1428V, A1428S,
908 15
861 15 c.2582_2583delTT, p.F861WfsX90,
1419 15 K1419E,