SCN5A Variant S901L Detail

We estimate the penetrance of LQTS for SCN5A S901L around 4% and the Brugada syndrome penetrance around 63%. SCN5A S901L was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. S901L is not present in gnomAD. S901L 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 S901L around 4% (0/11) and the Brugada syndrome penetrance around 63% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA -2.81 None 90 2
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
26173111 2015 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)
26173111 2015

S901L has 68 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 14
891 13 I891T, I891N,
880 12
890 10 I890T,
901 0 E901K, S901L,
919 11
363 13
896 13 C896S,
348 13 P348A,
895 15 L895F,
1426 14
894 10 I894M,
372 9
1711 15 c.5131delG,
904 7 W904X,
887 14
886 14 H886P, H886Q,
376 10 R376C, R376H,
871 13
897 11 G897R, G897E,
909 13
1423 12 D1423H,
876 14
1422 9 M1422R,
1418 14
902 5
892 14 F892I,
349 9 D349N,
373 8
1712 15 G1712S, G1712C,
881 13
898 7
893 7 R893C, R893H,
922 15 V922I,
920 15
889 13
1420 12 G1420D, G1420R, G1420P, G1420V,
900 6
872 13 D872N,
918 15
1425 14
865 13
916 14
906 10
351 13 G351D, G351V, G351C, G351S,
910 15 S910L,
878 9 R878C, R878L, R878H,
1421 11
374 15 W374G,
350 8 H350Q,
903 8 p.M903CfsX29,
367 11 R367L, R367C, R367H,
370 14 T370M,
877 10
879 8 W879R,
923 14
905 6
375 12
352 12 Y352C,
915 12 C915R,
899 9
380 15
377 13
908 11
861 15 c.2582_2583delTT, p.F861WfsX90,
1419 12 K1419E,
353 12 T353I,
907 11