KCNH2 Variant C66R

Summary of observed carriers, functional annotations, and structural context for KCNH2 C66R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

33%

90% CI: 17.4% – 63.8%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

C66R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 4%. 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 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-8.133 1.0 -4 0.885 88

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
Japan Cohort 2020 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
Variant features alone – 10 7 3 –

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

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 C66R.
Neighbour residue Distance (Å) Observed variants
66 0 C66R, C66G, C66Y,
65 4 T65P,
67 5
68 5 F68L, F68V, F68L, F68L,
69 5 L69Del, L69P,
63 6 P63H,
64 6 C64R, C64Y,
70 6 H70R, H70Q, H70Q,
62 8 R62Q,
98 8
59 9
82 9 I82Del, I82dup, I82Ins, I82T,
41 9 V41A,
30 9 I30Del, I30T,
127 10
79 10 A79T, A79S, A79Del, A79fsX,
48 10
54 10 Y54N, Y54X,
39 10 C39R, C39X,
40 10
52 11 C52W,
96 11 I96V, I96T,
129 11 F129C,
83 11 A83P, A83fsX,
110 11 V110A,
71 11 G71R, G71R, G71W, G71E,
32 11 A32T,
38 12
58 12 E58K, E58D, E58D,
60 12 M60T,
74 12 T74fsX, T74M,
97 12
99 12 Y99N, Y99S,
86 12 L86R,
80 12 A80P,
108 12 C108Y,
125 13
78 13 A78T, A78P,
61 13 Q61R,
51 13
31 13 I31S,
44 13 C44F, C44X, C44W,
106 13 F106L, F106V, F106L, F106L,
112 13 V112M,
53 13 G53S, G53R,
94 13 V94L, V94L, V94A,
100 13 R100G, R100Q, R100P,
101 13 K101E,
49 13 C49R, C49G,
55 13 S55L,
85 14 A85P, A85V,
42 14 I42N,
29 14 F29L, F29V, F29S, F29L, F29L,
128 14 N128S,
57 14 A57P,
76 14
81 14 Q81E, Q81X, Q81P, Q81H, Q81H,
126 14
28 14 K28E,
75 14 Q75X,
109 15 L109X, L109Q, L109P,
72 15 P72T, P72S, P72Q, P72R,
111 15 D111V,
73 15 R73G, R73C, R73fsX, R73H,
43 15 Y43D, Y43C,
33 15 N33T
45 15 N45D, N45K, N45K,
105 15
56 15 R56Q,