SCN5A Variant C280Y Detail

We estimate the penetrance of LQTS for SCN5A C280Y around 8% and the Brugada syndrome penetrance around 58%. SCN5A C280Y was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. C280Y is not present in gnomAD. C280Y 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 C280Y around 8% (0/11) and the Brugada syndrome penetrance around 58% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-10.65 1 -4.54 0.973 78 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
23321620 2013 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)
23321620 2013

C280Y has 48 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
328 11
333 11 c.998+5G>A, c.998+1G>A,
277 12
326 5
276 13 L276Q, L276P,
348 12 P348A,
317 15 K317N, K317E, K317M,
279 5
385 14 A385T,
338 9
278 8 H278R, H278D,
334 9 c.999-424_1338+81del,
332 12 A332T,
343 12
327 8
339 6
384 10 S384T,
284 13
329 14
282 8 R282H, R282C,
340 8 R340W, R340Q,
285 14 T285K,
283 10
341 6 C341Y,
274 14 G274C,
335 7 C335R, C335S,
319 11 G319S, G319R, G319C,
325 7 L325R,
324 7
321 9 S321Y,
345 12
275 13 N275K,
383 9
280 0 C280Y,
323 6
347 14
337 12
320 10 T320N,
1689 14 D1689N,
342 7
346 14 E346G, E346K, E346D, E346X,
336 7 P336L,
344 10 A344S,
381 15 c.1140+1G>A, c.1141-3C>A,
322 10
1691 15
380 12
281 5 V281M,