SCN5A Variant S321Y Detail

We estimate the penetrance of LQTS for SCN5A S321Y around 3% and the Brugada syndrome penetrance around 50%. SCN5A S321Y was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. S321Y is not present in gnomAD. S321Y 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 (4 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 S321Y around 3% (0/11) and the Brugada syndrome penetrance around 50% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.55 0.667 -0.76 0.551 65 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
25401102 2014 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 4 - -
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)
25401102 2014

S321Y has 35 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
343 14
277 12
350 14 H350Q,
341 14 C341Y,
342 12
326 13
276 15 L276P, L276Q,
339 13
346 8 E346K, E346X, E346D, E346G,
319 7 G319C, G319R, G319S,
325 12 L325R,
348 11 P348A,
317 10 K317E, K317N, K317M,
282 11 R282H, R282C,
279 7
324 10
321 0 S321Y,
344 9 A344S,
872 12 D872N,
340 15 R340Q, R340W,
285 14 T285K,
345 8
322 4
278 13 H278R, H278D,
380 15
873 14 S873A,
280 9 C280Y,
349 12 D349N,
318 10
281 9 V281M,
323 6
347 11
283 14
351 13 G351C, G351V, G351S, G351D,
320 4 T320N,