KCNH2 Variant G648A Detail

We estimate the penetrance of LQTS for KCNH2 G648A is 77%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. G648A is not present in gnomAD. G648A has been functionally characterized in 1 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G648A around 77% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.801 1.0 0 0.934 83
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
France Cohort 2020 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 3 7 -
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)
17823114 Xeno 9.0 None None 1.060402685

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)
17823114 Xeno None None None

G648A has 75 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
648 0 G648A,
649 3
647 4
622 5 L622F,
651 5 M651K,
650 5 L650X,
644 6 V644F, V644I,
646 6
652 7 Y652X,
645 7 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
653 8
621 8 S621R, S621R, S621N, S621R,
623 8 T623I,
623 8 T623I,
643 9
624 9 S624R, S624R, S624N, S624R,
654 9
557 9
560 9 I560fsX, I560M,
656 9 F656L, F656L, F656L,
655 10
652 10 Y652X,
618 10 T618S, T618S,
656 10 F656L, F656L, F656L,
641 10 S641P, S641F,
642 10 I642V, I642Del,
625 11 V625E,
620 11 S620I, S620G,
624 11 S624R, S624R, S624N, S624R,
619 11
554 11
564 11 L564L,
619 11
561 11 A561T, A561V, A561P,
557 11
640 12 F640L, F640Del, F640L, F640V, F640L,
620 12 S620I, S620G,
625 12 V625E,
622 12 L622F,
649 12
659 12
617 13 F617V, F617L, F617L, F617L,
660 13 S660L,
556 13
558 13 A558V, A558P, A558E,
657 13 G657V, G657S,
624 13 S624R, S624R, S624N, S624R,
645 13 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
655 13
626 13 G626S, G626V, G626A,
627 14 F627X, F627L, F627L, F627fsX, F627L,
626 14 G626S, G626V, G626A,
558 14 A558V, A558P, A558E,
553 14 L553V,
657 14 G657V, G657S,
646 14
554 14
550 14
653 14
621 14 S621R, S621R, S621N, S621R,
563 14 W563G, W563C, W563X, W563C,
559 14 L559H, L559F,
658 14
663 14
624 14 S624R, S624R, S624N, S624R,
616 15 Y616S,
565 15
639 15 I639N, I639F,
615 15 L615V, L615F,
653 15
553 15 L553V,
648 15 G648A,
648 15 G648A,
652 15 Y652X,
651 15 M651K,