KCNH2 Variant I711V

Summary of observed carriers, functional annotations, and structural context for KCNH2 I711V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

90% CI: 2.1% – 23.3%

2/35 effective observations

Total carriers

25

1 LQT2 · 9 unaffected

Functional studies

1

Publications with functional data

I711V is present in 24 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 82% of WT with a standard error of 16%. 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 (%)
-0.957 0.614 3 0.848 19

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
26746457 2016 1 0 1
Literature, cohort, and gnomAD – 25 9 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)
25417810 HEK293 47 2.4 None None 0.613173653

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)
25417810 HEK293 None None None

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 I711V.
Neighbour residue Distance (Å) Observed variants
711 0 I711V,
710 4
712 5 D712N,
708 5
713 5 M713V,
709 6
682 6 E682X,
679 7 R679W, R679Q,
686 8
683 8
705 8 W705fsX, W705X,
672 9 R672C, R672H,
716 9 V716G,
715 9 A715T, A715A, A715V, A715sp,
707 9
704 9 A704T, A704V,
669 10 G669R, G669C, G669X,
714 10
680 10
706 10 S706C, S706F,
678 10
687 10
668 11 S668L,
684 11
685 12 R685C, R685H, R685P,
717 12 L717P
676 12 Q676fsX, Q676X,
676 12 Q676fsX, Q676X,
675 12
701 12
673 12
719 13
681 13 R681W,
670 13
703 13
671 13 A671G, A671Del,
718 13
677 13 M677T,
760 13
762 14
700 14
702 15
688 15
675 15
732 15
720 15
665 15 R665Q,
728 15
689 15