SCN5A Variant L325R

Summary of observed carriers, functional annotations, and structural context for SCN5A L325R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

5%

0/11 effective observations

Estimated BrS1 penetrance

62%

6/11 effective observations

Total carriers

1

1 BrS1 · 0 LQT3 · 0 unaffected

L325R has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for Brugada syndrome and a Non_Hotspot region for LQT3.

Variant features alone are equivalent to phenotyping 5 individuals for Brugada syndrome and 0 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.72 0.317 -2.29 0.919 87 7

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source 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

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Peak and late/persistent current values are relative to wild-type (100% indicates no change). V1/2 activation and inactivation denote the membrane potentials (mV) at which half-maximal current is achieved.

Published electrophysiology measurements.
PubMed ID Year Cell Type Peak Current (% WT) V1/2 Activation (mV) V1/2 Inactivation (mV) Late/Persistent Current (% WT)
15890323 2005 HEK 18 10.4 4.4
20129283 2010

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD.

Previously observed variants near L325R.
Neighbour residue Distance (Å) Observed variants
328 11
333 9 c.998+1G>A, c.998+5G>A
277 10
326 5
276 7 L276Q, L276P,
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, G386R,
340 14 R340Q, R340W,
378 12
331 14
349 11 D349N,
379 9
272 12
341 9 C341Y,
274 11 G274C,
335 10 C335S, C335R, C335S,
325 0 L325R,
1690 14 D1690N, c.5068_5070delGA,
324 5
321 12 S321Y,
389 14 Y389X, Y389H,
345 12
275 9 N275K, N275K,
383 5
280 7 C280Y,
323 6
347 10
382 9
351 13 G351D, G351S, G351C, G351V,
320 14 T320N,
1689 11 D1689N,
350 15 H350Q, H350Q,
342 10
346 12 E346D, 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,