KCNH2 Variant R56Q

Summary of observed carriers, functional annotations, and structural context for KCNH2 R56Q. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

65%

90% CI: 47.5% – 80.9%

13/21 effective observations

Total carriers

11

11 LQT2 · 0 unaffected

Functional studies

5

Publications with functional data

R56Q has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 53% of WT with a standard error of 24%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-2.544 0.699 0 0.877 76

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source 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 8 2 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
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

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
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

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that 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 15Å window.

Previously observed variants near R56Q.
Neighbour residue Distance (Å) Observed variants
56 0 R56Q,
44 4 C44F, C44X, C44W,
55 6 S55L,
859 6 T859M, T859R,
60 6 M60T,
57 6 A57P,
803 7 D803Y, D803X,
59 7
43 7 Y43D, Y43C,
49 7 C49R, C49G,
46 8 D46Y, D46E, D46E,
45 8 N45D, N45K, N45K,
799 8 L799sp,
800 8
857 9 E857X,
58 9 E58K, E58D, 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 Y54N, Y54X,
30 11 I30Del, I30T,
53 11 G53S, G53R,
61 11 Q61R,
782 11 I782fsX, I782N,
29 11 F29L, F29V, F29S, 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, V796L, V796Del,
856 13
786 13
19 13 I19F,
789 13
740 13 C740G, C740W,
785 13 G785S, G785fsX, G785D,
40 13
861 13 N861H, N861I,
781 13
51 14
788 14 E788K, E788D, E788D,
28 14 K28E,
783 14 S783P,
806 14 G806R, G806R,
68 14 F68L, F68V, F68L, F68L,
32 14 A32T
101 14 K101E,
855 15 S855R, S855R, S855R,
27 15 R27X, R27P,
63 15 P63H,
66 15 C66R, C66G, C66Y,