SCN5A Variant L846R Detail

We estimate the penetrance of LQTS for SCN5A L846R around 17% and the Brugada syndrome penetrance around 59%. SCN5A L846R was found in a total of 1 carriers in 2 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. L846R is not present in gnomAD. L846R has been functionally characterized in 2 papers. This residue is located in a Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (5 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L846R around 17% (1/11) and the Brugada syndrome penetrance around 59% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.94 0.999 -2.78 0.991 79 25
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID 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 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
22028457 2011 HEK-tSA201 0
28341781 2017

L846R has 74 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
891 10 I891T, I891N,
888 10
848 7 I848F,
890 14 I890T,
896 11 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, c.2552_2553dupGT, p.F851CfsX19,
412 15 V412D,
897 14 G897E, G897R,
924 13 V924I,
927 10 N927S, N927K,
852 10
854 12 c.2559delT,
845 5 c.2533delG,
892 9 F892I,
849 5
226 13 A226V, A226G,
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,
855 14
837 14
239 10 I239V, I239V ,
1454 12
230 11 I230V, I230M, I230T,
242 14 A242D,
929 10
1448 15 I1448T, I1448L,
416 15 Y416C,
884 15
841 10 N841K, p.N841TfsX2,
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,