SCN5A Variant L1650F Detail

We estimate the penetrance of LQTS for SCN5A L1650F around 70% and the Brugada syndrome penetrance around 12%. SCN5A L1650F was found in a total of 1 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. L1650F is not present in gnomAD. L1650F has been functionally characterized in 1 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 (3 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A L1650F around 70% (4/11) and the Brugada syndrome penetrance around 12% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.73 0.998 5.36 0.821 18 78
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
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 0 -
VARIANT FEATURES ALONE: - 15 11 3 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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
19716085 2009

L1650F 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
403 6
414 15 M414V,
1659 15
1643 10 I1643L,
404 9 L404Q, L404V,
1778 10
1773 12
1653 6
254 15
1771 7 I1771T,
401 13 S401P,
1652 7 M1652R, M1652T,
1634 11 L1634P,
1777 12 V1777M, V1777L,
250 15
409 13 L409P, L409V,
1650 0 L1650F,
260 12
1656 11
1641 15
1779 12 T1779M,
1776 12
369 15 M369K,
1787 15 S1787N,
1767 11 Y1767C,
1660 14 I1660V, I1660S,
1654 7
1648 7
1769 12
402 12 F402L,
1649 4 A1649V,
1768 12 I1768V,
1774 8 c.5321_5324dupACTT, N1774D,
1644 11 R1644H, R1644C, R1644L,
256 10
399 10
405 12
1657 9
1781 14 E1781D, E1781G,
1789 14
255 15
1772 10 L1772V,
1645 9 T1645M,
410 11 A410V,
1788 13 c.5361_5364delTGAG,
1770 10 I1770V,
1658 11
1651 6
259 14
1633 15
1637 13
408 12
253 11
407 8
1775 8 p.F1775LfsX15, F1775V,
1642 12 G1642E,
1655 10
1631 14 G1631D,
406 10 N406S, N406K,
252 14
411 13 V411M,
398 12
1647 5
257 13
400 11 G400A, G400R, G400E,
1646 6