KCNH2 Variant M651V Detail

We estimate the penetrance of LQTS for KCNH2 M651V is 75%. We are unaware of any observations of this variant in individuals. M651V is not present in gnomAD. M651V 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 M651V around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.876 0.993 1 0.899 87
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.

M651V 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
651 0 M651K,
650 5 L650X,
655 5
648 5 G648A,
654 5
647 6
653 6
649 7
652 7 Y652X,
557 7
560 8 I560fsX, I560M,
656 8 F656L, F656L, F656L,
622 8 L622F,
556 9
553 9 L553V,
646 10
644 10 V644F, V644I,
657 10 G657V, G657S,
658 10
623 10 T623I,
561 11 A561V, A561P, A561T,
656 11 F656L, F656L, F656L,
558 11 A558V, A558P, A558E,
660 11 S660L,
554 11
663 11
659 11
659 12
619 12
649 12
559 12 L559F, L559H,
621 12 S621N, S621R, S621R, S621R,
643 12
564 12 L564L,
645 12 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
618 12 T618S, T618S,
554 12
555 12
624 12 S624R, S624R, S624R, S624N,
652 12 Y652X,
563 13 W563X, W563C, W563G, W563C,
623 13 T623I,
552 13 L552S,
646 13
550 13
660 14 S660L,
653 14
657 14 G657V, G657S,
620 14 S620I, S620G,
650 14 L650X,
664 14 Q664X,
550 14
667 14 Y667X,
557 14
661 15 A661V,
645 15 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
641 15 S641F, S641P,
662 15
640 15 F640L, F640V, F640L, F640L, F640Del,
655 15
642 15 I642Del, I642V,
562 15 H562Q, H562Q, H562R, H562P,
624 15 S624R, S624R, S624R, S624N,
648 15 G648A,