KCNH2 Variant I419L Detail

We estimate the penetrance of LQTS for KCNH2 I419L is 66%. We are unaware of any observations of this variant in individuals. I419L is not present in gnomAD. I419L 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I419L around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.67 0.025 2 0.687 78
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 4 6 -
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.

I419L has 54 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
419 0
418 4
416 6
422 6 A422T,
415 6
421 6 T421M, T421fsX,
423 6
417 7
420 7 Y420C,
555 7
559 7 L559H, L559F,
532 8
424 9
414 9 I414fsX,
556 9
552 10 L552S,
551 10 F551L, F551L, F551L,
558 10 A558E, A558P, A558V,
535 10 V535M,
531 10 R531W, R531Del, R531Q,
413 10 L413P,
425 11
562 11 H562Q, H562R, H562Q, H562P,
529 11
563 11 W563C, W563X, W563G, W563C,
459 11
412 12 W412X,
426 12 P426H,
542 12
463 12 F463L, F463L, F463L,
534 12 R534C,
560 12 I560fsX, I560M,
528 12 R528X, R528P, R528W,
533 13
554 13
456 13 D456Y,
411 13
553 13 L553V,
561 13 A561T, A561P, A561V,
530 13
557 14
455 14
536 14 A536X,
462 14 M462Ins,
427 14 Y427S, Y427H, Y427C,
548 14
538 14
410 14 W410X,
460 14 D460fsX,
428 15 S428L, S428fsX, S428X,
539 15
458 15
527 15
549 15 V549M,