SCN5A Variant A887V Detail

We estimate the penetrance of LQTS for SCN5A A887V around 4% and the Brugada syndrome penetrance around 37%. SCN5A A887V was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. A887V is not present in gnomAD. A887V has been functionally characterized in 0 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 A887V around 4% (0/10) and the Brugada syndrome penetrance around 37% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.927 52 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: - 0 0 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.

A887V has 67 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 6 I891T, I891N,
880 7
888 5
848 14 I848F,
223 13 V223L,
856 9 V856L,
890 5 I890T,
901 14 E901K, S901L,
919 11
862 10
896 14 C896S,
859 11
895 12 L895F,
894 10 I894M,
1447 10
1444 11 L1444I,
1440 15 W1440X,
149 11
863 14
887 0
1451 13 V1451L, V1451D,
864 14
886 5 H886Q, H886P,
851 9 F851L, c.2552_2553dupGT, c.2550_2551dupGT, p.F851CfsX19,
852 11
854 5 c.2559delT,
876 13
1422 14 M1422R,
857 7 G857D,
150 15
902 10
882 9
892 9 F892I,
881 5
849 13
898 14
893 11 R893C, R893H,
922 12 V922I,
860 12 p.L860fsx89,
889 6
858 6 M858L,
918 12
855 8
1425 14
865 11
148 12
1448 14 I1448L, I1448T,
884 5
906 12
878 13 R878L, R878C, R878H,
885 7
847 13
846 14 L846R,
903 14 p.M903CfsX29,
1441 15 E1441Q,
152 11 D152N,
853 9
877 12
151 13
879 9 W879R,
883 6
905 13
915 13 C915R,
850 9 V850M, c.2549_2550insTG,
145 14
861 10 p.F861WfsX90, c.2582_2583delTT,
220 14 T220I,