KCNH2 Variant M554L Detail

We estimate the penetrance of LQTS for KCNH2 M554L is 30%. We are unaware of any observations of this variant in individuals. M554L is not present in gnomAD. M554L 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M554L around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.875 0.226 2 0.762 44
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 8 2 -
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.

M554L has 52 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
554 0
553 6 L553V,
555 6
557 6
550 6
556 7
551 7 F551L, F551L, F551L,
646 7
650 7 L650X,
558 7 A558P, A558E, A558V,
656 7 F656L, F656L, F656L,
552 8 L552S,
655 8
659 8
649 8
549 10 V549M,
647 10
559 10 L559F, L559H,
560 10 I560M, I560fsX,
548 11
648 11 G648A,
619 11
651 11 M651K,
652 11 Y652X,
658 11
547 11 A547T,
662 12
561 12 A561T, A561P, A561V,
653 12
660 12 S660L,
657 12 G657V, G657S,
643 12
645 12 M645I, M645L, M645L, M645I, M645R, M645V, M645I,
663 12
623 12 T623I,
651 12 M651K,
622 12 L622F,
654 12
654 12
642 12 I642V, I642Del,
419 13
546 13
653 13
644 13 V644I, V644F,
661 13 A661V,
562 14 H562Q, H562R, H562P, H562Q,
648 14 G648A,
615 14 L615V, L615F,
415 14
563 15 W563X, W563G, W563C, W563C,
618 15 T618S, T618S,
652 15 Y652X,