KCNH2 Variant F22Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 F22Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

26%

8/16 effective observations

Total carriers

6

6 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F22Y has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 131% of WT with a standard error of 19%. 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 (%)
-1.643 0.986 2 0.79 85

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 1 0 1
Italy Cohort 2020 4 0 4
Literature, cohort, and gnomAD – 6 0 6 –
Variant features alone – 10 8 2 –

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 F22Y.
Neighbour residue Distance (Å) Observed variants
22 0 F22Y, F22S,
21 5
25 5 Q25P,
27 6 R27X, R27P,
23 6
18 6 I18M,
29 6 F29L, F29V, F29S, F29L, F29L,
19 6 I19F,
24 7
26 8 S26I,
128 8 N128S,
126 8
17 9
28 9 K28E,
20 9 R20G, R20L,
45 10 N45D, N45K, N45K,
43 10 Y43D, Y43C,
113 11 V113Del,
30 11 I30Del, I30T,
16 11 D16A,
31 11 I31S,
127 11
111 11 D111V,
15 11 L15V,
129 11 F129C,
47 12 G47C, G47V,
130 12 E130K,
115 13 V115M,
14 13
44 13 C44F, C44X, C44W,
48 13
46 13 D46Y, D46E, D46E,
112 13 V112M,
114 13 P114S,
124 14 M124T, M124R,
798 14 I798fsX,
125 14
32 14 A32T
110 15 V110A,
42 15 I42N,
109 15 L109X, L109Q, L109P,
91 15
13 15 T13N,