KCNH2 Variant T65P

Summary of observed carriers, functional annotations, and structural context for KCNH2 T65P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

35%

10/25 effective observations

Total carriers

15

8 LQT2 · 7 unaffected

Functional studies

2

Publications with functional data

T65P 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 10%. 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 (%)
-3.567 0.997 -1 0.862 71

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 6 2 4
12354768 2002 5 2 3
15840476 2005 1 0 1
16922724 2006 1 1
29766883 2016 2 2
Literature, cohort, and gnomAD – 15 7 8 –
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)
12354768 HEK293 21 -3.72 None None None
23721480 CHO 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)
12354768 HEK293 50 None None None
23721480 CHO 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 T65P.
Neighbour residue Distance (Å) Observed variants
65 0 T65P,
66 4 C66G, C66R, C66Y,
64 4 C64Y, C64R,
63 5 P63H,
67 6
82 7 I82T, I82dup, I82Del, I82Ins,
83 7 A83fsX, A83P,
70 8 H70R, H70Q, H70Q,
79 8 A79fsX, A79Del, A79T, A79S,
39 8 C39X, C39R,
69 9 L69Del, L69P,
86 9 L86R,
68 9 F68L, F68V, F68L, F68L,
38 9
62 9 R62Q,
80 10 A80P,
127 10
40 10
41 10 V41A,
98 10
85 10 A85V, A85P,
32 11 A32T,
125 11
30 11 I30Del, I30T,
110 11 V110A,
78 11 A78T, A78P,
96 11 I96T, I96V,
59 11
84 11
112 12 V112M,
81 12 Q81E, Q81X, Q81P, Q81H, Q81H,
87 12 L87P,
94 12 V94A, V94L, V94L,
129 12 F129C,
74 12 T74M, T74fsX,
76 12
71 13 G71W, G71R, G71R, G71E,
31 13 I31S,
77 13 R77S,
34 13 A34T,
48 13
97 13
33 13 N33T,
36 13 V36X,
126 14
60 14 M60T,
61 14 Q61R,
37 14
108 14 C108Y,
92 14 R92C, R92L,
75 14 Q75X,
42 14 I42N,
111 14 D111V,
54 14 Y54N, Y54X,
52 14 C52W,
99 15 Y99N, Y99S,
128 15 N128S,
124 15 M124R, M124T,
88 15
113 15 V113Del,
114 15 P114S,