SCN5A Variant L928P Detail

We estimate the penetrance of LQTS for SCN5A L928P around 3% and the Brugada syndrome penetrance around 54%. SCN5A L928P was found in a total of 1 carriers in 1 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. L928P is not present in gnomAD. L928P has been functionally characterized in 2 papers. This residue is located in a Hotspot region for Brugada syndrome and a Non_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 (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L928P around 3% (0/11) and the Brugada syndrome penetrance around 54% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.39 0.484 -5.98 0.966 66 7
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
20129283 2010 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 0 1 -
VARIANT FEATURES ALONE: - 15 11 0 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)
20129283 2010
32533946 2020 HEK 1

L928P has 76 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
403 15
414 15 M414V,
891 14 I891N, I891T,
919 14
896 11 C896S,
404 10 L404Q, L404V,
895 10 L895F,
842 14
249 14 K249X,
894 11 I894M,
247 10 V247L,
254 10
372 13
1771 15 I1771T,
401 11 S401P,
926 6
371 12 Q371E,
250 9
409 8 L409V, L409P,
928 0 L928P,
925 7 I925F,
366 11
934 13
933 10
258 15 V258A,
246 10
935 11 L935P,
412 9 V412D,
897 10 G897R, G897E,
924 5 V924I,
927 4 N927S, N927K,
245 15 Q245K,
369 10 M369K,
244 15
402 14 F402L,
415 14 A415T,
1768 13 I1768V,
849 13
898 14
256 15
921 10
922 9 V922I,
405 7
248 15
261 15
920 10
930 8 c.2788-6C>T, c.2787+17_2787+18insACACACACACACACACACACACA,
1459 13 c.4376_4379delTCTT,
1772 14 L1772V,
918 14
251 13
410 11 A410V,
242 13 A242D,
929 5
416 15 Y416C,
413 12 A413T, A413E,
408 6
253 11
407 10
846 13 L846R,
367 15 R367C, R367H, R367L,
936 13
853 14
370 9 T370M,
923 6
406 10 N406K, N406S,
368 15
899 12
850 14 c.2549_2550insTG, V850M,
411 10 V411M,
243 11
932 6
257 12
400 14 G400E, G400A, G400R,
931 7
1463 14 N1463Y,