KCNH2 Variant Y427D Detail

We estimate the penetrance of LQTS for KCNH2 Y427D is 58%. We are unaware of any observations of this variant in individuals. Y427D is not present in gnomAD. Y427D 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 Y427D around 58% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.25 0.984 -3 0.944 58
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.

Y427D has 49 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
427 0 Y427C, Y427S, Y427H,
428 5 S428X, S428fsX, S428L,
431 5 F431L, F431L, F431L,
424 6
426 6 P426H,
611 7 Y611D,
430 7
429 7 A429V, A429P,
423 7
432 8
566 8 C566G, C566S, C566F, C566R, C566S,
425 8
562 8 H562Q, H562P, H562Q, H562R,
607 8
569 10 Y569C, Y569X, Y569H,
452 10
565 10
608 10
610 10
422 10 A422T,
420 11 Y420C,
612 11 V612A, V612L, V612L,
563 11 W563C, W563X, W563C, W563G,
615 12 L615V, L615F,
609 12 D609G, D609N,
614 12 A614V, A614T,
421 12 T421fsX, T421M,
525 12 K525N, K525N,
567 12 I567T, I567M,
570 12
606 12 S606Del, S606P, S606F,
456 12 D456Y,
559 13 L559H, L559F,
561 13 A561V, A561P, A561T,
453 13
522 13 G522E,
526 13
528 13 R528X, R528W, R528P,
564 13 L564L,
613 13 T613K, T613M, T613A, T613L,
419 14
573 14
558 14 A558P, A558V, A558E,
450 14
529 14
451 14 P451L,
455 14
523 14
568 15 W568C, W568C,