SCN5A Variant C335R

Summary of observed carriers, functional annotations, and structural context for SCN5A C335R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

12%

0/12 effective observations

Estimated BrS1 penetrance

63%

7/12 effective observations

Total carriers

2

2 BrS1 · 0 LQT3 · 0 unaffected

C335R has not been reported in gnomAD. This residue resides in a 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 (%)
-11.77 0.998 -2.44 0.957 79 6

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
28781330 2017 1 0 1 0
29402340 2017 2 0 1 1 atrial flutter
Literature, cohort, and gnomAD – 2 0 0 2 –
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)
28781330 2017
29402340 2017
32533946 2020 HEK 0

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 C335R.
Neighbour residue Distance (Å) Observed variants
328 8
333 7 c.998+1G>A, c.998+5G>A,
326 5
279 12
385 13 A385T,
338 8
330 12 S330F,
278 11 H278D, H278R,
334 4 c.999-424_1338+81del,
332 9 A332T,
327 7
339 7
384 11 S384T,
284 15
329 10
282 11 R282C, R282H,
340 9 R340W, R340Q,
386 14 G386R, G386R, G386E,
331 12
283 12
341 8 C341Y,
335 0 C335S, C335R, C335S,
325 10 L325R,
1690 12 c.5068_5070delGA, D1690N
324 11
383 10
280 7 C280Y,
323 12
382 15
337 8
1689 13 D1689N,
342 11
336 4 P336L,
1691 12
281 10 V281M,