KCNH2 Variant H485N Detail

We estimate the penetrance of LQTS for KCNH2 H485N is 17%. We are unaware of any observations of this variant in individuals. H485N is not present in gnomAD. H485N 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H485N around 17% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.092 0.043 1 0.62 24
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 9 1 -
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.

H485N has 30 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
485 0 H485X,
484 4
486 5
488 7 R488H, R488C,
487 7 G487S, G487R,
483 8 V483I,
399 8
489 8 I489F, I489I,
472 8 R472C, R472X,
398 9 W398X, W398L,
474 9 T474I,
473 10 T473P,
400 10 I400N,
482 11 V482A,
475 11 Y475Del, Y475C,
490 11 A490T, A490P,
401 12
471 12 F471X,
491 13 V491I,
480 14 E480V,
402 14 H402R,
492 14 H492Y,
9 14 A9V, A9T,
470 14 N470D,
481 14
8 14
469 14
476 14 V476I,
477 15
493 15 Y493F, Y493Ins, Y493C, Y493H,