KCNQ1 Variant H455Y Detail

We estimate the penetrance of LQTS for KCNQ1 H455Y is 30%. This variant was found in a total of 5 carriers in 2 papers or gnomAD, 3 had LQTS. H455Y is not present in gnomAD. H455Y has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H455Y around 30% (4/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.52 0.159 -3 0.586 17
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 LQT1 Other Disease
29672598 2018 1 1 None None
19808498 2009 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 5 2 3
VARIANT FEATURES ALONE: - 10 9 1 -
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19808498 CHO 43 0.0 0.6 None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19808498 CHO None None None

H455Y has 31 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. This results from the fact that the functional KV7.1 channel 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
455 0 H455Y, H455Q, H455Q, H455R,
454 4
456 4 F456L, F456L, F456L,
453 5
457 5
452 7 R452Q, R452W, R452L,
458 7
451 8 R451Q, R451W,
459 8 D459N, D459V,
450 8 E450K,
460 8 G460S, G460D, G460C,
449 9 E449K,
461 9
448 10 P448R, P448Q, P448L, P448S,
462 10
447 11 P447H,
463 11 S463T,
446 11 D446E, D446E, D446E, D446E, D446N,
464 11 S464P,
445 12
465 12
444 13 T444M, T444K,
466 13
443 13
467 13 K467R,
442 14 H442R,
468 14 S468G, S468N,
441 14 P441S,
469 14
440 15
470 15