KCNH2 Variant M574I Detail

We estimate the penetrance of LQTS for KCNH2 M574I is 29%. We are unaware of any observations of this variant in individuals. M574I is not present in gnomAD. M574I 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 M574I around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.145 0.034 2 0.643 42
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.

M574I has 32 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
574 0 M574V, M574L, M574L,
573 5
570 5
575 6 E575K,
572 6 G572C, G572S, G572D, G572R,
571 7 I571L, I571V,
576 8
569 9 Y569H, Y569C, Y569X,
430 10
567 10 I567T, I567M,
636 11
577 11
429 12 A429V, A429P,
568 12 W568C, W568C,
431 12 F431L, F431L, F431L,
523 12
566 12 C566S, C566F, C566G, C566R, C566S,
586 12 L586M,
637 12 E637G, E637X, E637K,
585 13 W585C, W585C,
432 13
634 13 T634A, T634S, T634S, T634P, T634I,
522 13 G522E,
584 14 G584R, G584C, G584S,
640 14 F640L, F640L, F640V, F640Del, F640L,
565 14
610 14
520 14
587 14
635 15 N635I,
583 15 I583V,
426 15 P426H,