KCNH2 Variant F29L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F29L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

63%

90% CI: 52.8% – 75.3%

30/49 effective observations

Total carriers

39

28 LQT2 · 10 unaffected

Functional studies

4

Publications with functional data

F29L is present in 1 alleles 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 11%. 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 (%)
-3.481 0.0 -1 0.927 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
11854117 2002 1 0 1
26403377 2015 33 7 26
24606995 2014 1 0 1
10973849 2000 1 0 1
15840476 2005 1 0 1
22882672 2012 9 3
Literature, cohort, and gnomAD – 39 10 28 –
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)
10187793 Xeno None None None None
21536673 Xeno 0 None None None None
23721480 CHO None None None None
26403377 HEK293 25 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)
10187793 Xeno None None None
21536673 Xeno None None None
23721480 CHO None None None
26403377 HEK293 60 81 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 F29L.
Neighbour residue Distance (Å) Observed variants
29 0 F29L, F29V, F29S, F29L, F29L,
30 5 I30Del, I30T,
45 5 N45D, N45K, N45K,
27 6 R27X, R27P,
43 6 Y43D, Y43C,
128 6 N128S,
22 6 F22Y, F22S,
28 6 K28E,
31 7 I31S,
127 7
126 7
19 7 I19F,
48 7
129 7 F129C,
44 7 C44F, C44X, C44W,
47 8 G47C, G47V,
18 9 I18M,
23 9
26 9 S26I,
46 10 D46Y, D46E, D46E,
25 10 Q25P,
111 10 D111V,
21 10
49 11 C49R, C49G,
32 11 A32T,
42 11 I42N,
113 11 V113Del,
41 11 V41A,
798 11 I798fsX,
15 11 L15V,
24 11
56 11 R56Q,
130 11 E130K,
51 12
112 12 V112M,
125 12
110 12 V110A,
59 12
124 12 M124T, M124R,
50 12 E50X,
16 12 D16A,
17 12
64 13 C64R, C64Y,
60 13 M60T,
52 13 C52W,
20 13 R20G, R20L,
109 13 L109X, L109Q, L109P,
800 13
114 13 P114S,
115 13 V115M,
108 13 C108Y,
66 14 C66R, C66G, C66Y,
797 14 A797T,
14 14
40 14
799 14 L799sp,
801 14 K801T,
55 14 S55L,
131 15 V131L, V131L, V131fsX,
786 15
33 15 N33T
53 15 G53S, G53R,
98 15
69 15 L69Del, L69P,