KCNH2 Variant Y420H Detail

We estimate the penetrance of LQTS for KCNH2 Y420H is 78%. We are unaware of any observations of this variant in individuals. Y420H is not present in gnomAD. Y420H 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 Y420H around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.758 1.0 2 0.967 93
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.

Y420H has 48 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
420 0 Y420C,
424 5
421 5 T421M, T421fsX,
423 6
417 6
456 7 D456Y,
419 7
459 7
422 7 A422T,
418 7
455 7
425 8
416 8
452 9
528 9 R528W, R528X, R528P,
531 9 R531W, R531Q, R531Del,
458 10
460 10 D460fsX,
426 10 P426H,
428 10 S428fsX, S428L, S428X,
453 10
427 11 Y427H, Y427C, Y427S,
463 11 F463L, F463L, F463L,
457 11 L457P,
415 11
529 11
414 11 I414fsX,
454 11
462 12 M462Ins,
413 12 L413P,
559 12 L559F, L559H,
562 12 H562Q, H562Q, H562P, H562R,
525 12 K525N, K525N,
532 12
451 12 P451L,
563 13 W563C, W563G, W563X, W563C,
461 13
429 13 A429P, A429V,
527 13
526 13
504 13 A504V,
555 14
530 14
534 14 R534C,
558 14 A558V, A558E, A558P,
450 14
535 15 V535M,
566 15 C566G, C566S, C566F, C566R, C566S,