KCNH2 Variant Q81H

Summary of observed carriers, functional annotations, and structural context for KCNH2 Q81H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

2/13 effective observations

Total carriers

3

1 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

Q81H 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: 72% of WT with a standard error of 13%. 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 (%)
-2.833 0.452 0 0.658 58

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
20167303 2010 2 1 seizure?
Literature, cohort, and gnomAD – 3 1 1 –
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 Q81H.
Neighbour residue Distance (Å) Observed variants
81 0 Q81E, Q81X, Q81P, Q81H, Q81H,
80 4 A80P,
78 5 A78T, A78P,
82 5 I82Del, I82dup, I82Ins, I82T,
79 6 A79T, A79S, A79Del, A79fsX,
94 6 V94L, V94L, V94A,
77 6 R77S,
84 6
83 7 A83P, A83fsX,
92 7 R92C, R92L,
85 8 A85P, A85V,
76 9
96 9 I96V, I96T,
110 10 V110A,
95 10 E95K, E95G,
75 10 Q75X,
86 11 L86R,
112 11 V112M,
93 11 K93X, K93R,
65 12 T65P,
90 12 E90K,
88 12
74 12 T74fsX, T74M,
87 12 L87P,
109 12 L109X, L109Q, L109P,
111 13 D111V,
91 13
97 13
70 13 H70R, H70Q, H70Q,
98 13
89 13 A89G, A89V,
108 13 C108Y,
64 14 C64R, C64Y,
127 14
66 14 C66R, C66G, C66Y,
73 15 R73G, R73C, R73fsX, R73H,
113 15 V113Del