KCNH2 Variant P426S Detail

We estimate the penetrance of LQTS for KCNH2 P426S is 52%. We are unaware of any observations of this variant in individuals. P426S is not present in gnomAD. P426S 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 P426S around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.613 0.995 -1 0.966 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.

P426S has 55 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
426 0 P426H,
425 4
429 5 A429P, A429V,
428 6 S428X, S428fsX, S428L,
566 6 C566F, C566R, C566S, C566G, C566S,
427 6 Y427S, Y427C, Y427H,
423 6
430 6
422 6 A422T,
563 7 W563C, W563C, W563X, W563G,
562 7 H562Q, H562P, H562R, H562Q,
424 7
526 8
431 8 F431L, F431L, F431L,
529 8
421 8 T421M, T421fsX,
525 9 K525N, K525N,
565 9
567 9 I567M, I567T,
528 9 R528W, R528P, R528X,
559 10 L559H, L559F,
432 10
420 10 Y420C,
611 10 Y611D,
523 10
522 11 G522E,
564 11 L564L,
527 11
569 11 Y569C, Y569H, Y569X,
561 11 A561T, A561P, A561V,
570 11
419 12
560 12 I560fsX, I560M,
456 12 D456Y,
531 12 R531W, R531Del, R531Q,
558 13 A558V, A558E, A558P,
418 13
524 13
615 13 L615V, L615F,
452 13
532 13
614 13 A614V, A614T,
530 13
607 14
568 14 W568C, W568C,
610 14
618 14 T618S, T618S,
573 15
571 15 I571V, I571L,
417 15
459 15
612 15 V612L, V612L, V612A,
556 15
574 15 M574V, M574L, M574L,
453 15