KCNH2 Variant I711V Detail

We estimate the penetrance of LQTS for KCNH2 I711V is 11%. This variant was found in a total of 10 carriers in 1 papers or gnomAD, 1 had LQTS. I711V is present in 9 alleles in gnomAD. I711V has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I711V around 11% (2/20).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.957 0.614 3 0.848 19
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
26746457 2016 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 10 9 1 -
VARIANT FEATURES ALONE: - 10 9 1 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

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

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

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

I711V has 49 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
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 R672H, R672C,
716 9 V716G,
715 9 A715V, A715A, A715T, A715sp,
707 9
704 9 A704T, A704V,
669 10 G669C, G669R, G669X,
714 10
680 10
706 10 S706C, S706F,
678 10
687 10
668 11 S668L,
684 11
685 12 R685P, R685C, R685H,
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 A671Del, A671G,
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