SCN5A Variant N275K Detail

We estimate the penetrance of LQTS for SCN5A N275K around 27% and the Brugada syndrome penetrance around 22%. SCN5A N275K was found in a total of 1 carriers in 2 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. N275K is not present in gnomAD. N275K has been functionally characterized in 2 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 (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 N275K around 27% (1/11) and the Brugada syndrome penetrance around 22% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.54 0.801 3.66 0.701 34 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
18452873 2008 2 1 0 1 AF
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
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)
18452873 2008
19716085 2009

N275K has 65 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 10
333 14 c.998+5G>A, c.998+1G>A,
364 14
277 7
271 8 L271V,
266 14 L266H,
326 11
276 5 L276Q, L276P,
387 15
348 12 P348A,
270 10 Q270K,
279 11
385 7 A385T,
355 9 F355I, F355C,
1549 13
330 15 S330F,
278 5 H278R, H278D,
388 13 I388S,
356 10 D356N,
334 14 c.999-424_1338+81del,
361 13
332 12 A332T,
343 8
327 9
384 6 S384T,
354 9
329 11
386 10 G386E, G386R,
378 14
267 13
379 15
1550 9
357 13
272 5
341 10 C341Y,
274 4 G274C,
273 7
325 9 L325R,
392 13
324 14
389 10 Y389H, Y389X,
269 10
1620 12 T1620K, T1620M,
345 12
393 14
275 0 N275K,
383 12
280 13 C280Y,
323 14
347 11
382 11
1548 14 G1548K, E1548K,
351 14 G351S, G351D, G351V, G351C,
265 14 A265V,
1619 13 P1619L, c.4856delC, P1619Q,
342 11
1551 12 D1551Y, D1551N,
346 14 E346X, E346K, E346D, E346G,
344 10 A344S,
381 8 c.1141-3C>A, c.1140+1G>A,
380 11
268 9 G268S,
377 12
353 12 T353I,
1623 13 R1623L, R1623Q, c.4867delC, R1623X,