SCN5A Variant L409Q Detail

We estimate the penetrance of LQTS for SCN5A L409Q around 60% and the Brugada syndrome penetrance around 11%. SCN5A L409Q was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L409Q is not present in gnomAD. L409Q 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L409Q around 60% (2/10) 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 0.974 4 81
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.

L409Q has 81 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 12
414 9 M414V,
939 10 L939F,
404 10 L404Q, L404V,
937 12
1773 11
1765 11
842 15
249 12 K249X,
247 13 V247L,
1653 15
254 14
1771 9 I1771T,
401 12 S401P,
1777 15 V1777M, V1777L,
418 14 E418K,
926 12
1764 13 c.5290delG, V1764F,
371 15 Q371E,
250 10
409 0 L409V, L409P,
928 8 L928P,
925 14 I925F,
1650 13 L1650F,
417 12
934 11
933 9
1471 14
246 10
935 7 L935P,
1779 14 T1779M,
412 5 V412D,
924 12 V924I,
1470 10
1464 14 c.4389_4396delCCTCTTTA, L1464P,
927 10 N927S, N927K,
1466 10 c.4396_4397insG,
245 14 Q245K,
1776 11
369 14 M369K,
1767 12 Y1767C,
1769 10
402 12 F402L,
1766 15 M1766T, M1766V, M1766L,
415 10 A415T,
1649 14 A1649V,
1768 8 I1768V,
940 13 S940N,
1774 13 c.5321_5324dupACTT, N1774D,
1473 15 F1473C, F1473S,
1468 15 V1468A, V1468F,
405 7
938 12
930 11 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
1459 14 c.4376_4379delTCTT,
1772 6 L1772V,
410 4 A410V,
242 13 A242D,
1770 12 I1770V,
929 9
416 11 Y416C,
413 6 A413T, A413E,
408 5
253 12
1462 15
407 7
936 8
1467 11
1775 9 p.F1775LfsX15, F1775V,
370 14 T370M,
923 14
1469 13 I1469V,
406 5 N406K, N406S,
411 7 V411M,
243 13
932 5
257 14
400 14 G400E, G400A, G400R,
931 10
1646 13
1463 11 N1463Y,