SCN5A Variant c.2787+17_2787+18insACACACACACACACACACACACA Detail

We estimate the penetrance of LQTS for SCN5A c.2787+17_2787+18insACACACACACACACACACACACA around 44% and the Brugada syndrome penetrance around 12%. SCN5A c.2787+17_2787+18insACACACACACACACACACACACA was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. c.2787+17_2787+18insACACACACACACACACACACACA is not present in gnomAD. c.2787+17_2787+18insACACACACACACACACACACACA has been functionally characterized in 1 papers. This residue is located in a Non_Hotspot region for Brugada syndrome and a Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 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 c.2787+17_2787+18insACACACACACACACACACACACA around 44% (2/11) and the Brugada syndrome penetrance around 12% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 10 42
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
24687331 2014 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 13 1 1 - -
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)
24687331 2014

c.2787+17_2787+18insACACACACACACACACACACACA has 73 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
414 15 M414V,
891 13 I891N, I891T,
848 11 I848F,
939 14 L939F,
896 11 C896S,
937 10
895 8 L895F,
839 11 L839P,
842 7
894 13 I894M,
247 11 V247L,
240 11 V240M,
1455 12
926 5
250 13
409 11 L409P, L409V,
928 8 L928P,
925 7 I925F,
227 15 L227P,
934 7
1458 13 S1458Y,
933 5
246 10
935 9 L935P,
412 9 V412D,
897 13 G897R, G897E,
924 9 V924I,
927 7 N927K, N927S,
852 14
245 14 Q245K,
845 8 c.2533delG,
244 12
415 12 A415T,
892 13 F892I,
849 8
921 13
922 10 V922I,
405 13
938 12
241 12
920 15
840 12
843 9 T843A,
930 0 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1459 10 c.4376_4379delTCTT,
1460 14 F1460L,
239 9 I239V, I239V ,
1454 14
230 13 I230M, I230T, I230V,
410 14 A410V,
242 10 A242D,
929 4
416 11 Y416C,
413 12 A413T, A413E,
841 12 p.N841TfsX2, N841K,
236 14
408 11
847 10
846 6 L846R,
936 10
238 13
233 15
838 13
853 12
923 10
406 15 N406S, N406K,
844 12 L844RfsX3,
850 10 c.2549_2550insTG, V850M,
411 13 V411M,
243 7
932 6
931 4
1463 12 N1463Y,