SCN5A Variant G897E Detail

We estimate the penetrance of LQTS for SCN5A G897E around 43% and the Brugada syndrome penetrance around 38%. SCN5A G897E was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. G897E is not present in gnomAD. G897E 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 (4 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 G897E around 43% (2/11) and the Brugada syndrome penetrance around 38% (4/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.59 1 -2.78 0.975 52 36
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
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 10 1 4 - -
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)
30059973 2018
25904541 2015 HEK 0

G897E has 77 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
364 14
891 10 I891N, I891T,
888 14
890 11 I890T,
901 11 S901L, E901K,
919 11
363 14
896 5 C896S,
895 7 L895F,
1417 11
894 5 I894M,
1455 15
372 6
401 13 S401P,
926 10
371 9 Q371E,
1711 12 c.5131delG,
928 10 L928P,
925 13 I925F,
904 14 W904X,
366 11
1451 15 V1451D, V1451L,
1458 12 S1458Y,
376 15 R376H, R376C,
897 0 G897E, G897R,
924 11 V924I,
927 7 N927S, N927K,
369 12 M369K,
1422 11 M1422R,
1418 7
902 10
892 9 F892I,
373 8
1712 14 G1712S, G1712C,
898 4
893 6 R893C, R893H,
921 13
922 9 V922I,
397 15 I397F, I397T, I397V,
405 12
1462 14
920 11
889 13
1709 13 T1709M, p.T1709del, T1709R,
1420 13 G1420P, G1420D, G1420R, G1420V,
900 9
930 13 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1459 11 c.4376_4379delTCTT,
918 14
1425 15
1713 15
1454 12
916 15
929 14
408 15
1421 10
374 12 W374G,
846 14 L846R,
903 12 p.M903CfsX29,
367 10 R367H, R367C, R367L,
1416 12 A1416E, c.4245+1G>A, c.4245+1G>C, c.4245+2T>A, A1416G,
853 14
1760 14
370 7 T370M,
879 14 W879R,
923 6
375 14
368 13
899 6
1710 11 S1710L,
1415 12
850 13 V850M, c.2549_2550insTG,
932 13
1419 9 K1419E,
1414 14 Q1414H,
931 10
1463 14 N1463Y,