SCN5A Variant R367C

Summary of observed carriers, functional annotations, and structural context for SCN5A R367C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

21%

2/18 effective observations

Estimated BrS1 penetrance

45%

8/18 effective observations

Total carriers

8

3 BrS1 · 2 LQT3 · 3 unaffected

R367C is present in 3 alleles in gnomAD. This residue resides in a Hotspot region for Brugada syndrome and a Mild_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 (%)
-7.85 1 -4.45 0.956 71 15

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
12106943 2002 1 0 1 0
21273195 2011 3 0 3 0
22885917 2012 1 0 1 0
26921764 2016 1 0 1 0
19251209 2009 1 0 1 0
19716085 2009 2 2 0 0
20129283 2010 2 0 2 0
30059973 2018 1 1 0 0
Literature, cohort, and gnomAD 8 3 2 3
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)
12106943 2002
21273195 2011
22885917 2012
26921764 2016
19251209 2009
19716085 2009
20129283 2010
30059973 2018
32533946 2020 HEK 1

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 R367C.
Neighbour residue Distance (Å) Observed variants
364 5
919 13
901 11 E901K, S901L,
276 13 L276P, L276Q,
363 6
896 15 C896S,
404 15 L404Q, L404V,
348 13 P348A,
360 11
396 11 V396A, V396L,
894 12 I894M,
355 11 F355I, F355C,
372 4
401 12 S401P,
371 8 Q371E,
1711 12 c.5131delG,
928 15 L928P,
361 10
904 9 W904X,
366 7
365 7
1706 13 Q1706H,
376 9 R376H, R376C,
354 11
897 10 G897E, G897R,
927 15 N927K, N927S,
369 9 M369K,
378 12
902 12
402 15 F402L,
349 11 D349N,
373 6
1712 14 G1712S, G1712C,
379 13
898 10
893 13 R893H, R893C,
922 15 V922I,
272 14
397 11 I397F, I397T, I397V,
405 14
362 10
261 12
920 11
1709 13 T1709R, T1709M, p.T1709del,
900 6
392 13
393 11
916 12
264 13
347 14
351 13 G351D, G351V, G351S, G351C
265 12 A265V,
374 8 W374G,
350 12 H350Q,
358 15
903 9 p.M903CfsX29,
367 0 R367L, R367C, R367H,
359 13 p.A359PfsX12, A359T,
370 7 T370M,
381 12 c.1140+1G>A, c.1141-3C>A,
923 11
905 14
375 10
352 12 Y352C,
368 5
899 6
1710 14 S1710L,
380 12
915 15 C915R,
268 13 G268S,
377 6
400 13 G400A, G400R, G400E,
1419 14 K1419E,
353 9 T353I,
907 13