SCN5A Variant L325R Detail

We estimate the penetrance of LQTS for SCN5A L325R around 5% and the Brugada syndrome penetrance around 62%. SCN5A L325R was found in a total of 1 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. L325R is not present in gnomAD. L325R 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 (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 L325R around 5% (0/11) and the Brugada syndrome penetrance around 62% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.72 0.317 -2.29 0.919 87 7
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
15890323 2005 1 0 1 0
20129283 2010 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)
15890323 2005 HEK 18 10.4 4.4
20129283 2010

L325R has 61 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 9 c.998+1G>A, c.998+5G>A,
277 10
326 5
276 7 L276P, L276Q,
387 15
348 8 P348A,
279 6
385 9 A385T,
355 14 F355I, F355C,
1687 14
330 15 S330F,
278 6 H278R, H278D,
334 9 c.999-424_1338+81del,
332 9 A332T,
343 12
327 7
339 13
376 11 R376H, R376C,
384 5 S384T,
354 12
329 12
1692 12
386 11 G386E, G386R,
340 14 R340W, R340Q,
378 12
331 14
349 11 D349N,
379 9
272 12
341 9 C341Y,
274 11 G274C,
335 10 C335S, C335R,
325 0 L325R,
1690 14 c.5068_5070delGA, D1690N,
324 5
321 12 S321Y,
389 14 Y389H, Y389X,
345 12
275 9 N275K,
383 5
280 7 C280Y,
323 6
347 10
382 9
351 13 G351C, G351D, G351S, G351V,
320 14 T320N,
1689 11 D1689N,
350 15 H350Q,
342 10
346 12 E346X, E346K, E346D, E346G,
336 12 P336L,
344 10 A344S,
381 8 c.1140+1G>A, c.1141-3C>A,
322 10
375 14
1691 11
380 6
377 11
281 11 V281M,
353 11 T353I,