SCN5A Variant L846R

Summary of observed carriers, functional annotations, and structural context for SCN5A L846R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT3 penetrance

17%

1/11 effective observations

Estimated BrS1 penetrance

59%

6/11 effective observations

Total carriers

1

1 BrS1 · 0 LQT3 · 0 unaffected

L846R has not been reported 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 1 individuals for LQT3.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.94 0.999 -2.78 0.991 79 25

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
22028457 2011 1 0 0 1 VF
28341781 2017 1 0 1 0
Literature, cohort, and gnomAD – 1 0 0 1 –
Variant features alone – 15 9 1 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)
22028457 2011 HEK-tSA201 0
28341781 2017

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 L846R.
Neighbour residue Distance (Å) Observed variants
891 10 I891N, I891T,
888 10
848 7 I848F,
890 14 I890T,
896 11 C896S, C896S,
937 13
895 8 L895F,
839 10 L839P,
842 6
894 12 I894M,
1457 15
240 12 V240M,
1455 10
1452 13
926 7
928 13 L928P,
925 9 I925F,
227 12 L227P,
887 14
1451 11 V1451L, V1451D,
934 10
1458 13 S1458Y,
933 10
229 13
246 15
935 13 L935P,
851 10 c.2550_2551dupGT, F851L, p.F851CfsX19, c.2552_2553dupGT, F851L, F851L,
412 15 V412D,
897 14 G897R, G897R, G897E,
924 13 V924I,
927 10 N927S, N927K, N927K,
852 10
854 12 c.2559delT,
845 5 c.2533delG,
892 9 F892I,
849 5
226 13 A226G, A226V,
921 14
922 10 V922I,
938 15
241 15
840 10
889 14
843 5 T843A,
1456 13
930 6 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1459 9 c.4376_4379delTCTT,
1460 14 F1460L, F1460L, F1460L,
855 14
837 14
239 10 I239V, I239V ,
1454 12
230 11 I230V, I230T, I230M,
242 14 A242D,
929 10
1448 15 I1448L, I1448T,
416 15 Y416C,
884 15
841 10 p.N841TfsX2, N841K, N841K,
236 14
847 4
846 0 L846R,
936 14
238 15
233 12
838 13
853 10
923 12
844 7 L844RfsX3,
850 6 V850M, c.2549_2550insTG,
243 11
932 12
931 8
1463 15 N1463Y