KCNH2 Variant I96T

Summary of observed carriers, functional annotations, and structural context for KCNH2 I96T. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

32%

90% CI: 12.7% – 50.2%

4/15 effective observations

Total carriers

5

2 LQT2 · 3 unaffected

Functional studies

1

Publications with functional data

I96T has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 56% of WT with a standard error of 16%. 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 (%)
-3.183 0.3 -1 0.912 55

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
France Cohort 2020 4 3 1
24606995 2014 1 0 1
Literature, cohort, and gnomAD – 5 3 2 –
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)
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)
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 I96T.
Neighbour residue Distance (Å) Observed variants
96 0 I96V, I96T,
97 4
98 5
95 5 E95K, E95G,
108 6 C108Y,
78 6 A78T, A78P,
94 7 V94L, V94L, V94A,
74 7 T74fsX, T74M,
107 7 L107P,
75 7 Q75X,
110 7 V110A,
79 7 A79T, A79S, A79Del, A79fsX,
70 8 H70R, H70Q, H70Q,
109 8 L109X, L109Q, L109P,
73 8 R73G, R73C, R73fsX, R73H,
106 8 F106L, F106V, F106L, F106L,
82 9 I82Del, I82dup, I82Ins, I82T,
69 9 L69Del, L69P,
81 9 Q81E, Q81X, Q81P, Q81H, Q81H,
71 9 G71R, G71R, G71W, G71E,
99 10 Y99N, Y99S,
77 10 R77S,
105 10
129 10 F129C,
76 10
80 10 A80P,
66 11 C66R, C66G, C66Y,
131 11 V131L, V131L, V131fsX,
65 11 T65P,
72 11 P72T, P72S, P72Q, P72R,
93 12 K93X, K93R,
130 12 E130K,
111 12 D111V,
127 12
67 12
112 13 V112M,
100 13 R100G, R100Q, R100P,
83 13 A83P, A83fsX,
51 13
68 13 F68L, F68V, F68L, F68L,
128 13 N128S,
92 13 R92C, R92L,
64 14 C64R, C64Y,
104 14
52 14 C52W,
85 14 A85P, A85V,
28 14 K28E
48 14
84 14