KCNH2 Variant I458M Detail

We estimate the penetrance of LQTS for KCNH2 I458M is 72%. We are unaware of any observations of this variant in individuals. I458M is not present in gnomAD. I458M 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I458M around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.418 0.903 1 0.612 83
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 3 7 -
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.

I458M has 34 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
458 0
459 5
457 5 L457P,
455 5
461 6
454 7
460 7 D460fsX,
456 7 D456Y,
462 7 M462Ins,
453 9
417 9
420 10 Y420C,
463 10 F463L, F463L, F463L,
464 11 I464X,
452 11
465 11
451 12 P451L,
413 12 L413P,
421 12 T421fsX, T421M,
528 12 R528X, R528W, R528P,
531 13 R531Q, R531W, R531Del,
416 13
414 13 I414fsX,
507 13 P507L, P507S,
424 13
418 13
505 13 A505V,
410 13 W410X,
466 13 D466E, D466E,
450 13
449 14
504 14 A504V,
425 15
419 15