KCNH2 Variant F48L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F48L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

26%

90% CI: 7.5% – 50.7%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F48L 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 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 (%)
-3.741 0.034 -1 0.912 72

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
Literature, cohort, and gnomAD – 0 0 0 –
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 F48L.
Neighbour residue Distance (Å) Observed variants
48 0
49 5 C49R, C49G,
47 5 G47C, G47V,
52 5 C52W,
45 6 N45D, N45K, N45K,
51 6
28 6 K28E,
44 6 C44F, C44X, C44W,
30 7 I30Del, I30T,
129 7 F129C,
29 7 F29L, F29V, F29S, F29L, F29L,
50 7 E50X,
53 8 G53S, G53R,
59 8
46 8 D46Y, D46E, D46E,
54 8 Y54N, Y54X,
55 9 S55L,
56 9 R56Q,
43 9 Y43D, Y43C,
127 9
27 9 R27X, R27P,
69 9 L69Del, L69P,
128 10 N128S,
66 10 C66R, C66G, C66Y,
100 10 R100G, R100Q, R100P,
98 10
68 11 F68L, F68V, F68L, F68L,
41 11 V41A,
31 11 I31S,
60 11 M60T,
106 11 F106L, F106V, F106L, F106L,
108 11 C108Y,
58 11 E58K, E58D, E58D,
130 11 E130K,
101 12 K101E,
110 12 V110A,
57 12 A57P,
26 12 S26I,
64 12 C64R, C64Y,
126 12
42 13 I42N,
62 13 R62Q,
131 13 V131L, V131L, V131fsX,
22 13 F22Y, F22S,
32 13 A32T
65 13 T65P,
19 13 I19F,
109 13 L109X, L109Q, L109P,
63 14 P63H,
111 14 D111V,
798 14 I798fsX,
23 14
70 14 H70R, H70Q, H70Q,
99 14 Y99N, Y99S,
104 14
96 14 I96V, I96T,
97 14
40 14
102 14 D102H, D102V, D102X,
67 15
859 15 T859M, T859R,
105 15
112 15 V112M,
107 15 L107P,
25 15 Q25P,
800 15