KCNH2 Variant R488H Detail

We estimate the penetrance of LQTS for KCNH2 R488H is 7%. This variant was found in a total of 4 carriers in 0 papers or gnomAD, 0 had LQTS. R488H is present in 4 alleles in gnomAD. R488H has not been functionally characterized. This residue is located in a Non_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 R488H around 7% (1/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.785 0.999 0 0.713 8
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: - 4 4 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.

R488H 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
488 0 R488H, R488C,
487 5 G487R, G487S,
484 6
483 6 V483I,
489 6 I489I, I489F,
485 7 H485X,
486 7
491 8 V491I,
490 9 A490T, A490P,
475 9 Y475C, Y475Del,
480 10 E480V,
492 10 H492Y,
482 10 V482A,
477 10
474 11 T474I,
481 12
473 12 T473P,
476 12 V476I,
472 12 R472X, R472C,
471 13 F471X,
479 13
494 13 F494Del,
9 13 A9V, A9T,
493 13 Y493C, Y493Ins, Y493F, Y493H,
478 14 A478D,
399 14
17 14
8 15
13 15 T13N,
400 15 I400N,
398 15 W398X, W398L,
470 15 N470D,