KCNH2 Variant Y54F

Summary of observed carriers, functional annotations, and structural context for KCNH2 Y54F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

18%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

Y54F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 126% of WT with a standard error of 17%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-0.928 0.004 5 0.47 84

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 9 1 –

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 Y54F.
Neighbour residue Distance (Å) Observed variants
54 0 Y54N, Y54X,
53 4 G53S, G53R,
101 5 K101E,
52 5 C52W,
58 5 E58K, E58D, E58D,
55 6 S55L,
68 7 F68L, F68V, F68L, F68L,
59 7
49 7 C49R, C49G,
69 8 L69Del, L69P,
48 8
100 9 R100G, R100Q, R100P,
57 9 A57P,
51 9
102 9 D102H, D102V, D102X,
62 10 R62Q,
66 10 C66R, C66G, C66Y,
56 11 R56Q,
50 11 E50X,
103 11
44 11 C44F, C44X, C44W,
60 11 M60T,
99 11 Y99N, Y99S,
98 12
104 12
857 12 E857X,
47 12 G47C, G47V,
67 12
70 12 H70R, H70Q, H70Q,
106 12 F106L, F106V, F106L, F106L,
45 13 N45D, N45K, N45K,
46 13 D46Y, D46E, D46E,
41 13 V41A,
30 13 I30Del, I30T
63 13 P63H,
105 14
61 14 Q61R,
859 14 T859M, T859R,
129 14 F129C,
71 14 G71R, G71R, G71W, G71E,
28 14 K28E,
65 14 T65P,
64 15 C64R, C64Y,
43 15 Y43D, Y43C,