KCNH2 Variant I464N Detail

We estimate the penetrance of LQTS for KCNH2 I464N is 56%. We are unaware of any observations of this variant in individuals. I464N is not present in gnomAD. I464N 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I464N around 56% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.285 0.996 -4 0.954 54
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 5 5 -
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.

I464N has 42 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
464 0 I464X,
465 5
461 5
467 6
505 6 A505V,
463 6 F463L, F463L, F463L,
468 7 L468X, L468R, L468F,
462 7 M462Ins,
466 7 D466E, D466E,
460 7 D460fsX,
504 9 A504V,
459 9
502 9 M502I, M502I, M502I,
507 9 P507L, P507S,
506 9 I506V,
469 10
501 10 D501H, D501Y, D501N,
531 10 R531Del, R531W, R531Q,
458 11
457 11 L457P,
470 11 N470D,
503 11
498 11
534 11 R534C,
471 11 F471X,
528 12 R528P, R528W, R528X,
410 12 W410X,
417 12
414 12 I414fsX,
456 13 D456Y,
493 13 Y493H, Y493Ins, Y493C, Y493F,
508 14
500 14 I500Del,
527 14
530 14
418 14
413 14 L413P,
421 14 T421fsX, T421M,
472 14 R472X, R472C,
499 15
473 15 T473P,
455 15