KCNH2 Variant I489S Detail

We estimate the penetrance of LQTS for KCNH2 I489S is 21%. We are unaware of any observations of this variant in individuals. I489S is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. I489S 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 I489S around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.56 1.0 -3 0.989 73
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.

I489S has 39 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
489 0 I489F, I489I,
490 4 A490T, A490P,
486 6
487 6 G487S, G487R,
475 6 Y475Del, Y475C,
492 6 H492Y,
491 6 V491I,
488 6 R488H, R488C,
471 7 F471X,
483 7 V483I,
484 7
473 7 T473P,
493 7 Y493H, Y493F, Y493C, Y493Ins,
474 7 T474I,
485 8 H485X,
472 8 R472X, R472C,
470 9 N470D,
494 9 F494Del,
477 11
476 11 V476I,
482 11 V482A,
400 11 I400N,
469 11
399 12
498 12
402 12 H402R,
480 12 E480V,
468 12 L468R, L468X, L468F,
496 12
467 12
401 12
398 13 W398X, W398L,
495 13 K495X,
481 13
497 14 W497L, W497X,
466 14 D466E, D466E,
537 14 R537W,
478 14 A478D,
407 15