SCN5A Variant L342P Detail

We estimate the penetrance of LQTS for SCN5A L342P around 31% and the Brugada syndrome penetrance around 16%. SCN5A L342P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L342P is not present in gnomAD. L342P has been functionally characterized in 0 papers. This residue is located in a Mild_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 L342P around 31% (1/10) and the Brugada syndrome penetrance around 16% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.925 14 40
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 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.

L342P has 46 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 10
333 15 c.998+5G>A, c.998+1G>A,
277 9
326 9
276 12 L276Q, L276P,
348 14 P348A,
317 11 K317E, K317N, K317M,
279 6
385 14 A385T,
338 12
278 6 H278R, H278D,
334 13 c.999-424_1338+81del,
318 14
332 15 A332T,
343 6
327 9
339 10
384 11 S384T,
284 14
329 14
282 11 R282H, R282C,
340 6 R340Q, R340W,
283 10
1550 13
341 4 C341Y,
274 11 G274C,
273 15
335 11 C335R, C335S,
319 12 G319S, G319R, G319C,
325 10 L325R,
324 13
321 12 S321Y,
345 9
275 11 N275K,
383 14
280 7 C280Y,
323 11
347 13
320 10 T320N,
342 0
1551 14 D1551Y, D1551N,
346 13 E346D, E346X, E346G, E346K,
336 12 P336L,
344 6 A344S,
322 14
281 5 V281M,