KCNH2 Variant I461M Detail

We estimate the penetrance of LQTS for KCNH2 I461M is 13%. We are unaware of any observations of this variant in individuals. I461M is not present in gnomAD. We have tested the trafficking efficiency of this variant, 31% of WT with a standard error of 12%; 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. I461M 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I461M around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.595 0.786 1 0.856 64
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.

I461M has 37 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
461 0
462 5 M462Ins,
460 5 D460fsX,
464 5 I464X,
458 6
459 6
465 6
457 6 L457P,
463 7 F463L, F463L, F463L,
505 9 A505V,
456 9 D456Y,
466 10 D466E, D466E,
507 10 P507S, P507L,
455 10
417 11
467 11
468 11 L468F, L468X, L468R,
454 11
531 11 R531Q, R531Del, R531W,
504 11 A504V,
528 12 R528W, R528P, R528X,
410 12 W410X,
506 12 I506V,
414 12 I414fsX,
469 12
453 13
413 13 L413P,
420 13 Y420C,
421 13 T421fsX, T421M,
502 14 M502I, M502I, M502I,
418 14
534 14 R534C,
501 14 D501H, D501N, D501Y,
470 15 N470D,
508 15
503 15
416 15