SCN5A Variant L407R Detail

We estimate the penetrance of LQTS for SCN5A L407R around 49% and the Brugada syndrome penetrance around 17%. SCN5A L407R was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L407R is not present in gnomAD. L407R 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L407R around 49% (2/10) and the Brugada syndrome penetrance around 17% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.994 14 65
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 12 2 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.

L407R 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 8
414 10 M414V,
1643 10 I1643L,
404 5 L404V, L404Q,
1778 13
1773 12
1765 15
249 11 K249X,
247 13 V247L,
1653 11
254 9
1771 7 I1771T,
401 10 S401P,
1652 13 M1652T, M1652R,
1777 14 V1777M, V1777L,
371 15 Q371E,
250 8
409 7 L409V, L409P,
928 10 L928P,
1650 8 L1650F,
260 12
366 14
933 14
258 13 V258A,
246 12
935 14 L935P,
1779 12 T1779M,
412 9 V412D,
924 13 V924I,
1470 15
927 14 N927S, N927K,
1466 15 c.4396_4397insG,
1776 11
369 11 M369K,
1767 12 Y1767C,
1654 13
1648 13
1769 12
402 11 F402L,
415 13 A415T,
1649 9 A1649V,
1768 10 I1768V,
1774 11 c.5321_5324dupACTT, N1774D,
1644 15 R1644H, R1644L, R1644C,
256 9
399 13
397 15 I397F, I397T, I397V,
405 7
1657 13
261 14
255 12
1772 8 L1772V,
1645 12 T1645M,
251 11
410 5 A410V,
1770 12 I1770V,
929 12
1651 13
259 14
413 10 A413T, A413E,
408 5
253 7
407 0
936 14
1775 7 F1775V, p.F1775LfsX15,
370 14 T370M,
1642 11 G1642E,
406 6 N406S, N406K,
252 11
411 6 V411M,
932 11
398 14
1647 9
257 9
400 10 G400R, G400A, G400E,
1646 7