KCNH2 Variant M645T Detail

We estimate the penetrance of LQTS for KCNH2 M645T is 71%. We are unaware of any observations of this variant in individuals. M645T is not present in gnomAD. M645T has not been functionally characterized. 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 M645T around 71% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.801 0.999 -1 0.904 76
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 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.

M645T has 84 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
645 0 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
644 5 V644I, V644F,
642 5 I642V, I642Del,
641 5 S641P, S641F,
619 5
623 6 T623I,
646 6
621 6 S621R, S621R, S621R, S621N,
620 6 S620G, S620I,
643 7
648 7 G648A,
625 7 V625E,
649 7
616 8 Y616S,
647 8
622 8 L622F,
627 8 F627L, F627fsX, F627L, F627X, F627L,
624 8 S624R, S624R, S624N, S624R,
624 9 S624R, S624R, S624N, S624R,
640 9 F640L, F640L, F640V, F640Del, F640L,
622 9 L622F,
626 9 G626S, G626A, G626V,
621 9 S621R, S621R, S621R, S621N,
615 9 L615F, L615V,
618 9 T618S, T618S,
620 10 S620G, S620I,
557 10
639 10 I639F, I639N,
623 10 T623I,
618 10 T618S, T618S,
638 10 K638R, K638Del, K638E, K638D,
617 10 F617V, F617L, F617L, F617L,
626 11 G626S, G626A, G626V,
617 11 F617V, F617L, F617L, F617L,
650 11 L650X,
652 11 Y652X,
632 11 P632S, P632A,
625 11 V625E,
561 11 A561V, A561T, A561P,
558 11 A558E, A558V, A558P,
652 12 Y652X,
564 12 L564L,
651 12 M651K,
625 12 V625E,
554 12
612 12 V612A, V612L, V612L,
656 12 F656L, F656L, F656L,
614 12 A614T, A614V,
637 13 E637G, E637X, E637K,
631 13 S631F,
613 13 T613L, T613M, T613A, T613K,
619 13
568 13 W568C, W568C,
648 13 G648A,
624 13 S624R, S624R, S624N, S624R,
629 13 N629T, N629K, N629D, N629S, N629K, N629I,
630 13 V630A, V630I, V630T,
624 13 S624R, S624R, S624N, S624R,
653 13
628 13 G628R, G628Del, G628S, G628V, G628D, G628A,
561 14 A561V, A561T, A561P,
560 14 I560fsX, I560M,
636 14
626 14 G626S, G626A, G626V,
627 14 F627L, F627fsX, F627L, F627X, F627L,
560 14 I560fsX, I560M,
630 14 V630A, V630I, V630T,
644 14 V644I, V644F,
627 14 F627L, F627fsX, F627L, F627X, F627L,
565 14
564 14 L564L,
651 15 M651K,
626 15 G626S, G626A, G626V,
557 15
628 15 G628R, G628Del, G628S, G628V, G628D, G628A,
611 15 Y611D,
562 15 H562R, H562Q, H562Q, H562P,
625 15 V625E,
567 15 I567T, I567M,
565 15
645 15 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
645 15 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
635 15 N635I,
655 15