SCN5A Variant P336L Detail

We estimate the penetrance of LQTS for SCN5A P336L around 12% and the Brugada syndrome penetrance around 38%. SCN5A P336L was found in a total of 3 carriers in 6 papers and/or in gnomAD: 1 had Brugada syndrome, 0 had LQTS. P336L is not present in gnomAD. P336L has been functionally characterized in 6 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 (3 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 P336L around 12% (0/13) and the Brugada syndrome penetrance around 38% (4/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-9.68 0.998 -2.24 0.916 50 15
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
17075016 2006 3 0 1 0
24269159 2013 2 0 1 0
26173111 2015 1 0 1 0
20129283 2010 1 0 1 0
20129283 2010 1 0 1 0
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 2 0 1 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
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)
17075016 2006 HEK-tSA201 15 1.7 -1.5 0
20129283 2010
26173111 2015
24269159 2013 HEK 20 0
20129283 2010
30059973 2018

P336L has 32 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
328 12
333 10 c.998+5G>A, c.998+1G>A,
1689 13 D1689N,
341 10 C341Y,
342 12
326 7
335 4 C335R, C335S,
327 10
339 4
384 14 S384T,
325 12 L325R,
1684 14 W1684R,
284 13
336 0 P336L,
1690 12 D1690N, c.5068_5070delGA,
329 14
282 9 R282H, R282C,
279 12
324 11
340 10 R340Q, R340W,
338 6
285 15 T285K,
278 14 H278R, H278D,
1691 14
334 7 c.999-424_1338+81del,
383 11
280 7 C280Y,
281 10 V281M,
323 12
283 11
337 6
332 12 A332T,