SCN5A Variant Y416C Detail

We estimate the penetrance of LQTS for SCN5A Y416C around 8% and the Brugada syndrome penetrance around 31%. SCN5A Y416C was found in a total of 2 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. Y416C is present in 1 alleles in gnomAD. Y416C has been functionally characterized in 2 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 Y416C around 8% (0/12) and the Brugada syndrome penetrance around 31% (3/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-8.83 1 -6.68 0.925 30 10
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
28341781 2017 1 0 1 0
28069705 2017 1 0 0 1 ARVD
LITERATURE, COHORT, AND GNOMAD: - 2 1 0 1 -
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.

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)
28341781 2017
28069705 2017

Y416C has 64 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
414 9 M414V,
939 9 L939F,
937 7
839 12 L839P,
842 10
249 12 K249X,
943 13 S943N,
247 13 V247L,
240 11 V240M,
418 8 E418K,
250 15
409 11 L409P, L409V,
237 12
928 15 L928P,
417 5
934 10
933 6
246 9
935 10 L935P,
1779 15 T1779M,
412 7 V412D,
1470 14
245 10 Q245K,
1776 14
845 13 c.2533delG,
244 12
415 6 A415T,
940 7 S940N,
420 5
938 10
241 9
235 12 c.704-1G>C, G235R, c.703+1G>A,
840 13
942 13
843 14 T843A,
419 6 Q419X,
930 11 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
423 10
1772 14 L1772V,
837 13
239 7 I239V , I239V,
410 11 A410V,
242 6 A242D,
929 11
416 0 Y416C,
413 6 A413T, A413E,
841 12 N841K, p.N841TfsX2,
236 13
408 14
941 10 S941F, S941N,
846 15 L846R,
936 5
238 7
838 10
422 10
1467 14
1775 15 p.F1775LfsX15, F1775V,
421 9
411 11 V411M,
243 9
932 11
835 13 S835A, S835L,
931 13
1463 15 N1463Y,