KCNH2 Variant L432R Detail

We estimate the penetrance of LQTS for KCNH2 L432R is 52%. We are unaware of any observations of this variant in individuals. L432R is not present in gnomAD. L432R 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L432R around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.643 0.963 -2 0.925 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.

L432R has 38 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
432 0
428 6 S428fsX, S428L, S428X,
429 6 A429V, A429P,
431 6 F431L, F431L, F431L,
430 6
427 8 Y427S, Y427H, Y427C,
522 9 G522E,
607 9
520 10
426 10 P426H,
569 10 Y569X, Y569C, Y569H,
525 11 K525N, K525N,
425 11
573 11
523 11
566 11 C566G, C566F, C566S, C566R, C566S,
610 12
424 12
452 12
570 12
521 13
611 13 Y611D,
574 13 M574L, M574L, M574V,
453 13
450 13
606 13 S606P, S606F, S606Del,
526 13
423 14
608 14
524 14
456 14 D456Y,
565 14
572 14 G572D, G572S, G572C, G572R,
567 14 I567M, I567T,
605 14 P605L,
562 15 H562Q, H562Q, H562R, H562P,
528 15 R528X, R528W, R528P,
609 15 D609G, D609N,