SCN5A Variant S941F Detail

We estimate the penetrance of LQTS for SCN5A S941F around 55% and the Brugada syndrome penetrance around 8%. SCN5A S941F was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. S941F is not present in gnomAD. S941F has been functionally characterized in 1 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (0 diagnosed with Brugada syndrome) and 5 individuals for LQTS (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A S941F around 55% (3/11) and the Brugada syndrome penetrance around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.86 0.999 -3.27 0.931 1 62
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
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 13 2 0 - -
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)
30059973 2018

S941F has 50 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
939 7 L939F,
937 6
839 10 L839P,
842 12
943 6 S943N,
1461 13 T1461S,
836 11 V836M,
417 11
934 10
933 12
1471 11
935 11 L935P,
1470 13
1464 10 L1464P, c.4389_4396delCCTCTTTA,
1466 13 c.4396_4397insG,
944 9
830 11
833 10 G833R,
940 4 S940N,
1468 12 V1468A, V1468F,
831 6
420 10
938 6
840 13
942 4
843 15 T843A,
419 15 Q419X,
834 8 N834D,
827 11
1460 10 F1460L,
837 11
239 14 I239V , I239V,
416 10 Y416C,
413 13 A413E, A413T,
841 14 N841K, p.N841TfsX2,
941 0 S941N, S941F,
1337 15
936 8
238 13
838 9
1467 10
1465 15 p.F1465_L1480dup,
421 13
1469 15 I1469V,
829 12
932 15
832 9
835 7 S835A, S835L,
828 10 L828V,
1463 13 N1463Y,