KCNH2 Variant D111V

Summary of observed carriers, functional annotations, and structural context for KCNH2 D111V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

14%

2/13 effective observations

Total carriers

3

1 LQT2 · 2 unaffected

Functional studies

1

Publications with functional data

D111V has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 80% of WT with a standard error of 15%. 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 (%)
-4.525 0.051 -3 0.796 40

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 3 2 1
20975234 2010 1 0 1
Literature, cohort, and gnomAD – 3 2 1 –
Variant features alone – 10 9 1 –

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)
20975234 CHO 20 None 10.9 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)
20975234 CHO 28 None 18.2 0.615384615

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 D111V.
Neighbour residue Distance (Å) Observed variants
111 0 D111V,
112 4 V112M,
128 5 N128S,
110 5 V110A,
93 5 K93X, K93R,
113 6 V113Del,
127 6
109 6 L109X, L109Q, L109P,
91 7
129 7 F129C,
126 7
94 8 V94L, V94L, V94A,
92 9 R92C, R92L,
114 9 P114S,
130 9 E130K,
90 10 E90K,
108 10 C108Y,
29 10 F29L, F29V, F29S, F29L, F29L,
28 10 K28E,
30 11 I30Del, I30T,
82 11 I82Del, I82dup, I82Ins, I82T,
85 11 A85P, A85V,
125 11
22 11 F22Y, F22S,
95 11 E95K, E95G,
27 11 R27X, R27P,
86 12 L86R,
96 12 I96V, I96T,
131 12 V131L, V131L, V131fsX,
115 12 V115M,
25 12 Q25P,
31 13 I31S,
89 13 A89G, A89V,
81 13 Q81E, Q81X, Q81P, Q81H, Q81H,
64 13 C64R, C64Y,
98 13
32 14 A32T
48 14
18 14 I18M,
83 14 A83P, A83fsX,
107 14 L107P,
124 14 M124T, M124R,
21 14
65 14 T65P,
26 14 S26I,
88 14
78 15 A78T, A78P,
66 15 C66R, C66G, C66Y,
79 15 A79T, A79S, A79Del, A79fsX,
45 15 N45D, N45K, N45K,