SCN5A Variant R376L Detail

We estimate the penetrance of LQTS for SCN5A R376L around 5% and the Brugada syndrome penetrance around 24%. SCN5A R376L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. R376L is not present in gnomAD. R376L has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 R376L around 5% (0/10) and the Brugada syndrome penetrance around 24% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.787 29 2
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 0 2 - -
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.

R376L has 66 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 12
1702 14
901 10 S901L, E901K,
276 11 L276P, L276Q,
363 14
348 8 P348A,
279 15
355 14 F355C, F355I,
1715 12
1687 10
372 10
371 13 Q371E,
1711 11 c.5131delG,
904 11 W904X,
1706 11 Q1706H,
1716 13 p.L1716SfsX71,
376 0 R376H, R376C,
1714 14 D1714G,
384 13 S384T,
1688 14
354 12
897 15 G897R, G897E,
1423 15 D1423H,
1692 12
1422 15 M1422R,
378 9
902 14
349 7 D349N,
373 7
1712 10 G1712S, G1712C,
379 6
1703 14
898 12
893 15 R893C, R893H,
1709 14 T1709M, p.T1709del, T1709R,
325 11 L325R,
1420 13 G1420V, G1420P, G1420R, G1420D,
900 10
324 10
393 13
1713 15
383 11
323 13
347 12
382 12
351 12 G351S, G351C, G351V, G351D,
374 9 W374G,
1689 12 D1689N,
350 11 H350Q,
903 14 p.M903CfsX29,
367 9 R367C, R367H, R367L,
370 15 T370M,
381 10 c.1140+1G>A, c.1141-3C>A,
1686 12
322 13
905 14
375 5
1691 14
352 14 Y352C,
368 12
899 13
1710 14 S1710L,
380 6
377 6
1419 12 K1419E,
353 9 T353I,