KCNH2 Variant I647F Detail

We estimate the penetrance of LQTS for KCNH2 I647F is 66%. We are unaware of any observations of this variant in individuals. I647F is not present in gnomAD. I647F has been functionally characterized in 2 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I647F around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.842 0.236 0 0.861 75
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 4 6 -
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)
11602243 Xeno 100 100 None None None None
12618227 Xeno 125 100 None None None None

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)
11602243 Xeno None None None
12618227 Xeno None None None

I647F has 59 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
647 0
648 4 G648A,
646 5
644 5 V644F, V644I,
650 6 L650X,
643 6
651 6 M651K,
649 6
622 7 L622F,
645 8 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
560 8 I560fsX, I560M,
564 9 L564L,
642 9 I642Del, I642V,
621 10 S621N, S621R, S621R, S621R,
554 10
640 10 F640L, F640V, F640L, F640L, F640Del,
641 10 S641F, S641P,
653 10
652 10 Y652X,
654 10
618 10 T618S, T618S,
561 10 A561V, A561P, A561T,
557 11
623 11 T623I,
655 11
619 11
656 11 F656L, F656L, F656L,
623 11 T623I,
557 12
563 12 W563X, W563C, W563G, W563C,
624 12 S624R, S624R, S624R, S624N,
619 12
556 13
652 13 Y652X,
639 13 I639F, I639N,
567 13 I567M, I567T,
620 13 S620I, S620G,
659 13
656 13 F656L, F656L, F656L,
550 13
558 13 A558V, A558P, A558E,
617 13 F617V, F617L, F617L, F617L,
558 13 A558V, A558P, A558E,
559 13 L559F, L559H,
625 13 V625E,
565 14
620 14 S620I, S620G,
624 14 S624R, S624R, S624R, S624N,
622 14 L622F,
660 14 S660L,
663 14
555 15
568 15 W568C, W568C,
655 15
562 15 H562Q, H562Q, H562R, H562P,
553 15 L553V,
551 15 F551L, F551L, F551L,
553 15 L553V,
616 15 Y616S,