SCN5A Variant R1644H Detail

We estimate the penetrance of LQTS for SCN5A R1644H around 64% and the Brugada syndrome penetrance around 7%. SCN5A R1644H was found in a total of 24 carriers in 15 papers and/or in gnomAD: 1 had Brugada syndrome, 17 had LQTS. R1644H is not present in gnomAD. R1644H has been functionally characterized in 17 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_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 R1644H around 64% (18/34) and the Brugada syndrome penetrance around 7% (2/34).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-4.56 0.995 -0.14 0.974 22 38
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
26803770 2016 15 10 0 0
8541846 1995 2 2 0 0
15051636 2004 2 1 0 0
15840476 2005 2 2 0 0
19026623 2009 1 1 0 0
20541041 2010 1 1 0 0
22360817 2012 1 1 0 0
23631430 2013 1 1 0 0
26669661 2016 16 11 0 0
26940925 2016 1 1 0 0
28341781 2017 1 0 1 0
25904541 2015 1 1 0 0
27566755 2016 2 2 0 0
29691127 2018 1 1 0 0
30059973 2018 2 2 0 0
LITERATURE, COHORT, AND GNOMAD: - 24 6 17 1 -
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.

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)
29691127 2018
30059973 2018
8541846 1995
15051636 2004
15840476 2005
19026623 2009
20541041 2010
22360817 2012
23631430 2013
26669661 2016
26803770 2016 hiPSC-CM 163
26940925 2016
28341781 2017
29017927 2017
25904541 2015
27566755 2016
8917568 1996 Oocytes -6.4 -2.5 800

R1644H has 45 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
1643 7 I1643L,
1778 12
1653 15
1635 10
1652 12 M1652R, M1652T,
1634 8 L1634P,
1650 11 L1650F,
1641 6
1639 7 G1639A,
1779 13 T1779M,
1787 10 S1787N,
1654 15
1786 14 c.5356_5357delCT, L1786R, L1786Q,
1648 7
1649 10 A1649V,
1644 0 R1644C, R1644L, R1644H,
1640 7
256 12
1793 11 M1793K,
1781 14 E1781D, E1781G,
1789 6
1632 15 R1632C, R1632H, R1632L,
255 13
1645 5 T1645M,
1796 13
1788 10 c.5361_5364delTGAG,
1638 6 R1638X, R1638Q,
1651 9
259 14
1633 11
1791 13
1637 5
253 13
1792 10 D1792V, D1792N, D1792Y,
1636 9
407 15
1775 13 F1775V, p.F1775LfsX15,
1642 7 G1642E,
1790 10 D1790G, p.D1790del, D1790N,
1631 13 G1631D,
252 12
1647 6
1822 14 c.5464_5467delTCTG, c.5464-5467delTCTG,
1646 8
1782 12