KCNH2 Variant C64R

Summary of observed carriers, functional annotations, and structural context for KCNH2 C64R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

31%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

C64R 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 6%. 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 (%)
-7.575 1.0 -4 0.822 82

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
Italy 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 C64R.
Neighbour residue Distance (Å) Observed variants
64 0 C64R, C64Y,
65 4 T65P,
63 5 P63H,
39 5 C39R, C39X,
66 6 C66R, C66G, C66Y,
32 7 A32T,
40 7
41 7 V41A,
125 7
86 7 L86R,
127 8
30 8 I30Del, I30T,
82 8 I82Del, I82dup, I82Ins, I82T,
38 8
83 9 A83P, A83fsX,
62 9 R62Q,
67 9
31 9 I31S,
33 10 N33T
34 10 A34T,
112 10 V112M,
59 10
85 10 A85P, A85V,
68 10 F68L, F68V, F68L, F68L,
42 10 I42N,
126 10
36 11 V36X,
69 11 L69Del, L69P,
124 11 M124T, M124R,
110 11 V110A,
60 11 M60T,
79 11 A79T, A79S, A79Del, A79fsX,
70 11 H70R, H70Q, H70Q,
87 12 L87P,
61 12 Q61R,
129 12 F129C,
48 12
37 12
114 12 P114S,
80 12 A80P,
98 13
113 13 V113Del,
29 13 F29L, F29V, F29S, F29L, F29L,
44 13 C44F, C44X, C44W,
35 13 R35W,
84 13
111 13 D111V,
43 13 Y43D, Y43C,
128 13 N128S,
796 13 V796L, V796L, V796Del,
122 13
94 13 V94L, V94L, V94A,
123 14
96 14 I96V, I96T,
81 14 Q81E, Q81X, Q81P, Q81H, Q81H,
92 14 R92C, R92L,
88 14
89 14 A89G, A89V,
78 14 A78T, A78P,
795 14 V795I,
90 14 E90K,
115 14 V115M,
52 15 C52W,
797 15 A797T,
54 15 Y54N, Y54X,
58 15 E58K, E58D, E58D,
798 15 I798fsX,
108 15 C108Y,