SCN5A Variant L917V Detail

We estimate the penetrance of LQTS for SCN5A L917V around 2% and the Brugada syndrome penetrance around 30%. SCN5A L917V was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L917V is present in 1 alleles in gnomAD. L917V has been functionally characterized in 0 papers. This residue is located in a Mild_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 L917V around 2% (0/11) and the Brugada syndrome penetrance around 30% (3/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
0.04 0.992 1.16 0.577 51 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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
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.

L917V has 42 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
364 15
891 14 I891N, I891T,
856 13 V856L,
919 7
363 11
360 13
894 13 I894M,
254 14
926 15
925 12 I925F,
904 13 W904X,
366 12
258 15 V258A,
221 14
924 11 V924I,
857 13 G857D,
902 13
921 6
922 10 V922I,
362 12
860 11 p.L860fsx89,
911 12 G911E,
920 5
900 13
918 5
917 0 L917R, L917V,
913 8
916 4
912 10 Q912R,
906 11
910 12 S910L,
903 9 p.M903CfsX29,
359 13 p.A359PfsX12, A359T,
853 12
923 11
352 15 Y352C,
915 7 C915R,
899 11
914 6
861 11 p.F861WfsX90, c.2582_2583delTT,
220 14 T220I,
907 10