KCNH2 Variant A653M Detail

We estimate the penetrance of LQTS for KCNH2 A653M is 52%. We are unaware of any observations of this variant in individuals. A653M is not present in gnomAD. A653M 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A653M around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 56
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 5 5 -
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)
19892754 Xeno -25.5 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)
19892754 Xeno None None None

A653M has 64 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
653 0
654 4
652 5 Y652X,
650 6 L650X,
660 6 S660L,
657 6 G657V, G657S,
651 6 M651K,
655 6
656 6 F656L, F656L, F656L,
649 6
656 7 F656L, F656L, F656L,
648 8 G648A,
659 8
657 8 G657V, G657S,
652 8 Y652X,
658 8
663 9
659 10
661 10 A661V,
660 10 S660L,
653 10
653 10
647 10
655 11
622 11 L622F,
664 11 Q664X,
658 11
649 11
557 11
623 11 T623I,
646 12
554 12
553 12 L553V,
662 12
623 12 T623I,
624 12 S624R, S624R, S624N, S624R,
654 12
661 12 A661V,
652 12 Y652X,
550 12
557 13
650 13 L650X,
624 13 S624R, S624R, S624N, S624R,
553 13 L553V,
554 13
645 13 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
657 14 G657V, G657S,
654 14
560 14 I560fsX, I560M,
644 14 V644I, V644F,
660 14 S660L,
651 14 M651K,
556 14
652 14 Y652X,
662 14
621 14 S621R, S621R, S621R, S621N,
648 14 G648A,
667 14 Y667X,
624 14 S624R, S624R, S624N, S624R,
653 14
657 14 G657V, G657S,
622 15 L622F,
649 15
648 15 G648A,