SCN5A Variant R965C

Summary of observed carriers, functional annotations, and structural context for SCN5A R965C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

5%

1/34 effective observations

Estimated BrS1 penetrance

27%

9/34 effective observations

Total carriers

24

7 BrS1 · 1 LQT3 · 16 unaffected

R965C is present in 16 alleles 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 2 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 (%)
-7.82 1 -4.59 0.944 22 3

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
19272188 2009 1 0 1 0
11076825 2000 2 0 2 0
11901046 2002 1 0 1 0
23293604 2012 1 0 1 0
23321620 2013 1 0 1 0
23631430 2013 1 1 0 0
24631775 2014 1 0 0 1 SD
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
30059973 2018 2 2 0 0
Literature, cohort, and gnomAD – 24 16 1 7 –
Variant features alone – 15 13 0 2 – –

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)
23321620 2013
23631430 2013
24524602 2013
24631775 2014
20129283 2010
20129283 2010
20129283 2010
30059973 2018
19272188 2009 HEK 79 0 -10
11076825 2000
11901046 2002
23293604 2012

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 R965C.
Neighbour residue Distance (Å) Observed variants
950 15 P950X,
951 14 D951X, c.2850delT,
952 14 E952K,
953 13 D953E, D953E, D953Y,
954 13 R954G,
955 12 p.E955DfsX74,
956 11 M956I, M956I, M956I, M956T,
957 11
958 10
959 9 L959P,
960 8 Q960K,
961 8
962 7
963 5
964 4 A964G,
965 0 R965H, R965L, R965C,
966 4
967 5 Q967R,
968 7
969 8 G969S, G969C,
970 8
971 9 R971C, R971H,
972 10 c.2914_2923delTTTGTCAAGC,
973 11
974 11 K974D,
975 12 R975W, R975Q,
976 13
977 13
978 14
979 14 D979H,
980 15