SCN5A Variant L895F Detail

We estimate the penetrance of LQTS for SCN5A L895F around 3% and the Brugada syndrome penetrance around 21%. SCN5A L895F was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L895F is present in 1 alleles in gnomAD. L895F 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 (2 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 L895F around 3% (0/11) and the Brugada syndrome penetrance around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.83 0.005 -0.82 0.89 29 6
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 13 0 2 - -
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.

L895F has 78 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 7 I891T, I891N,
848 13 I848F,
890 10 I890T,
901 15 E901K, S901L,
919 11
896 4 C896S,
895 0 L895F,
1417 14
842 13
894 5 I894M,
1457 13
1453 14
1455 11
1447 14
372 12
1452 14
926 5
371 15 Q371E,
928 10 L928P,
1450 14
925 9 I925F,
887 12
1451 11 V1451L, V1451D,
934 12
1458 11 S1458Y,
933 13
935 13 L935P,
851 13 p.F851CfsX19, c.2552_2553dupGT, c.2550_2551dupGT, F851L,
897 7 G897R, G897E,
924 10 V924I,
927 6 N927S, N927K,
852 13
854 12 c.2559delT,
845 12 c.2533delG,
1422 13 M1422R,
1418 10
902 13
892 5 F892I,
373 15
849 9
888 10
898 9
893 8 R893C, R893H,
921 12
922 7 V922I,
405 14
1462 14
920 12
889 10
843 12 T843A,
900 14
1456 15
930 8 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1459 8 c.4376_4379delTCTT,
918 13
1425 15
1454 10
929 10
1448 15 I1448T, I1448L,
408 15
1421 12
847 10
846 8 L846R,
903 14 p.M903CfsX29,
1416 13 A1416E, A1416G, c.4245+1G>A, c.4245+1G>C, c.4245+2T>A,
853 10
370 12 T370M,
879 14 W879R,
923 7
899 11
1415 14
844 15 L844RfsX3,
850 8 c.2549_2550insTG, V850M,
243 15
932 11
1419 14 K1419E,
931 7
1463 13 N1463Y,