KCNH2 Variant I414L Detail

We estimate the penetrance of LQTS for KCNH2 I414L is 57%. We are unaware of any observations of this variant in individuals. I414L is not present in gnomAD. I414L 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 I414L around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.903 0.973 2 0.877 70
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.

I414L has 59 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
414 0 I414fsX,
413 5 L413P,
417 5
415 5
411 5
410 6 W410X,
418 6
416 7
534 7 R534C,
463 7 F463L, F463L, F463L,
466 8 D466E, D466E,
462 8 M462Ins,
412 8 W412X,
535 8 V535M,
538 8
542 9
409 9 V409L, V409L, V409M,
407 9
531 9 R531W, R531Q, R531Del,
419 9
459 10
408 10
532 10
421 10 T421M, T421fsX,
465 10
541 11 R541H, R541C,
537 11 R537W,
469 11
533 11
420 11 Y420C,
470 11 N470D,
406 12
501 12 D501N, D501Y, D501H,
536 12 A536X,
467 12
464 12 I464X,
461 12
460 12 D460fsX,
539 13
422 13 A422T,
504 13 A504V,
458 13
552 13 L552S,
530 13
528 14 R528W, R528X, R528P,
540 14 D540fsX,
468 14 L468X, L468F, L468R,
505 14 A505V,
529 14
551 14 F551L, F551L, F551L,
473 14 T473P,
555 14
405 15
456 15 D456Y,
404 15
423 15
497 15 W497L, W497X,
455 15
548 15