KCNH2 Variant L69P

Summary of observed carriers, functional annotations, and structural context for KCNH2 L69P. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

41%

90% CI: 18.6% – 65.3%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

1

Publications with functional data

L69P 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 2%. 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 (%)
-4.5 1.0 -3 0.949 78

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
32253972 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.

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)
32253972 HEK293 100 0 -3.0 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)
32253972 HEK293 10 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 L69P.
Neighbour residue Distance (Å) Observed variants
69 0 L69Del, L69P,
68 4 F68L, F68V, F68L, F68L,
70 5 H70R, H70Q, H70Q,
98 5
66 5 C66R, C66G, C66Y,
67 7
99 7 Y99N, Y99S,
52 7 C52W,
71 8 G71R, G71R, G71W, G71E,
54 8 Y54N, Y54X,
97 8
100 8 R100G, R100Q, R100P,
65 9 T65P,
106 9 F106L, F106V, F106L, F106L,
96 9 I96V, I96T,
74 9 T74fsX, T74M,
48 9
51 10
101 10 K101E,
59 10
53 10 G53S, G53R,
105 10
108 10 C108Y,
63 10 P63H,
62 11 R62Q,
129 11 F129C,
64 11 C64R, C64Y,
103 11
104 11
72 11 P72T, P72S, P72Q, P72R,
79 11 A79T, A79S, A79Del, A79fsX,
73 11 R73G, R73C, R73fsX, R73H,
58 11 E58K, E58D, E58D,
110 12 V110A,
30 12 I30Del, I30T
102 12 D102H, D102V, D102X,
82 12 I82Del, I82dup, I82Ins, I82T,
49 12 C49R, C49G,
127 12
107 12 L107P,
55 13 S55L,
78 13 A78T, A78P,
75 13 Q75X,
41 13 V41A,
28 13 K28E,
109 14 L109X, L109Q, L109P,
94 14 V94L, V94L, V94A,
44 14 C44F, C44X, C44W,
47 14 G47C, G47V,
95 14 E95K, E95G,
76 14
60 14 M60T,
50 14 E50X,
80 15 A80P,
83 15 A83P, A83fsX,
128 15 N128S,
57 15 A57P,
131 15 V131L, V131L, V131fsX,
29 15 F29L, F29V, F29S, F29L, F29L,