KCNH2 Variant R56Q Detail

We estimate the penetrance of LQTS for KCNH2 R56Q is 86%. This variant was found in a total of 11 carriers in 3 papers or gnomAD, 11 had LQTS. R56Q is not present in gnomAD. R56Q has been functionally characterized in 5 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R56Q around 86% (18/21).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.544 0.699 0 0.877 76
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 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 LQT2 Other Disease
11854117 2002 8 0 8
30533098 2012 3 0 3
10973849 2000 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 11 0 11 -
VARIANT FEATURES ALONE: - 10 3 7 -
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 Homozygously Collected

Steady state (S.S.) and peak tail 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. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
10187793 Xeno 8 11.2 35.8 None None
15475579 HEK293 33 -2.0 9.7 None 0.3
21536673 Xeno 50 -3.3 26.6 None 0.333333333
23721480 CHO None None None None
25809256 Xeno None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
10187793 Xeno 100 33 7.3 18.9 None
15475579 HEK293 33 -1.5 7.2 0.4
21536673 Xeno None None None
23721480 CHO None None None
25809256 Xeno None None None

R56Q has 62 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. NOTE: some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. 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
56 0 R56Q,
44 4 C44F, C44X, C44W,
55 6 S55L,
859 6 T859R, T859M,
60 6 M60T,
57 6 A57P,
803 7 D803Y, D803X,
59 7
43 7 Y43C, Y43D,
49 7 C49G, C49R,
46 8 D46E, D46Y, D46E,
45 8 N45K, N45K, N45D,
799 8 L799sp,
800 8
857 9 E857X,
58 9 E58D, E58K, E58D,
798 9 I798fsX,
48 9
802 9
804 9
860 10
41 10 V41A,
858 10 I858V, I858T,
42 10 I42N,
797 10 A797T,
47 10 G47C, G47V,
801 10 K801T,
54 11 Y54X, Y54N,
30 11 I30Del, I30T,
53 11 G53R, G53S,
61 11 Q61R,
782 11 I782fsX, I782N,
29 11 F29S, F29V, F29L, F29L, F29L,
52 11 C52W,
31 11 I31S,
50 12 E50X,
741 12 K741R,
805 12 F805S, F805C,
62 12 R62Q,
787 12
796 13 V796L, V796Del, V796L,
856 13
786 13
19 13 I19F,
789 13
740 13 C740G, C740W,
785 13 G785D, G785fsX, G785S,
40 13
861 13 N861H, N861I,
781 13
51 14
788 14 E788D, E788K, E788D,
28 14 K28E,
783 14 S783P,
806 14 G806R, G806R,
68 14 F68V, F68L, F68L, F68L,
32 14 A32T,
101 14 K101E,
855 15 S855R, S855R, S855R,
27 15 R27P, R27X,
63 15 P63H,
66 15 C66R, C66G, C66Y,