KCNH2 Variant P486H Detail

We estimate the penetrance of LQTS for KCNH2 P486H is 25%. We are unaware of any observations of this variant in individuals. P486H is not present in gnomAD. P486H has not been functionally characterized. This residue is located in a Mild_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 P486H around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.957 0.868 -2 0.864 28
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
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.

P486H has 26 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
486 0
487 4 G487R, G487S,
485 5 H485X,
489 6 I489I, I489F,
472 6 R472C, R472X,
490 7 A490T, A490P,
488 7 R488H, R488C,
484 7
471 8 F471X,
491 10 V491I,
398 10 W398X, W398L,
473 10 T473P,
483 10 V483I,
399 10
474 10 T474I,
475 11 Y475Del, Y475C,
400 11 I400N,
493 12 Y493C, Y493F, Y493Ins, Y493H,
492 12 H492Y,
470 12 N470D,
494 12 F494Del,
468 12 L468R, L468F, L468X,
469 13
401 14
482 14 V482A,
467 14