SCN5A Variant L404R Detail

We estimate the penetrance of LQTS for SCN5A L404R around 38% and the Brugada syndrome penetrance around 11%. SCN5A L404R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L404R is not present in gnomAD. L404R has been functionally characterized in 0 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 L404R around 38% (1/10) and the Brugada syndrome penetrance around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.986 5 49
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.

L404R has 72 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 6
1643 12 I1643L,
404 0 L404Q, L404V,
249 15 K249X,
396 10 V396A, V396L,
247 15 V247L,
1653 13
254 9
1771 10 I1771T,
401 6 S401P,
1634 15 L1634P,
1764 14 V1764F, c.5290delG,
371 11 Q371E,
250 10
409 10 L409V, L409P,
928 10 L928P,
1650 9 L1650F,
260 8
366 10
365 12
258 11 V258A,
246 15
412 13 V412D,
924 12 V924I,
927 13 N927S, N927K,
369 6 M369K,
1767 11 Y1767C,
1654 13
1769 14
402 8 F402L,
1649 12 A1649V,
1768 11 I1768V,
1774 15 c.5321_5324dupACTT, N1774D,
262 13 S262G,
256 8
399 9
397 10 I397V, I397F, I397T,
405 5
1657 13
362 14
261 9
920 15
255 11
1772 12 L1772V,
395 13
251 13
410 10 A410V,
1770 14 I1770V,
264 12
929 13
1651 14
259 11
413 15 A413T, A413E,
408 6
253 8
407 5
367 15 R367C, R367H, R367L,
263 13 V263I,
1775 12 p.F1775LfsX15, F1775V,
370 10 T370M,
1642 14 G1642E,
923 13
406 7 N406K, N406S,
368 12
252 13
411 11 V411M,
932 12
398 11
1647 11
257 6
400 5 G400R, G400E, G400A,
1646 10