SCN5A Variant C915R Detail

We estimate the penetrance of LQTS for SCN5A C915R around 10% and the Brugada syndrome penetrance around 59%. SCN5A C915R was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. C915R is not present in gnomAD. C915R has been functionally characterized in 1 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 C915R around 10% (0/11) and the Brugada syndrome penetrance around 59% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-10.92 0.998 -3.51 0.961 80 3
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
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
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)
20129283 2010

C915R has 56 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 12 I891T, I891N,
880 14
856 11 V856L,
890 11 I890T,
901 12 S901L, E901K,
919 6
862 11
363 12
859 13
360 13
894 12 I894M,
863 14
904 9 W904X,
887 13
366 15
864 11
909 9
854 13 c.2559delT,
857 9 G857D,
868 14 c.2602delC, L868X,
902 8
881 10
893 14 R893H, R893C,
921 11
922 11 V922I,
860 8 p.L860fsx89,
911 7 G911E,
920 9
900 11
858 13 M858L,
918 6
855 15
917 7 L917R, L917V,
865 11
913 6
916 5
912 7 Q912R,
906 4
351 15 G351V, G351D, G351C, G351S,
910 7 S910L,
350 13 H350Q,
903 6 p.M903CfsX29,
367 15 R367C, R367L, R367H,
359 15 p.A359PfsX12, A359T,
853 12
877 15
923 13
905 9
352 12 Y352C,
915 0 C915R,
899 11
908 10
914 5
861 6 p.F861WfsX90, c.2582_2583delTT,
220 14 T220I,
907 5