KCNQ1 Variant H502Q Detail

We estimate the penetrance of LQTS for KCNQ1 H502Q is 9%. We are unaware of any observations of this variant in individuals. H502Q is not present in gnomAD. H502Q has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H502Q around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.89 0.952 0 0.666 2
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 10 0 -
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.

H502Q 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
502 0
501 4 T501A,
503 4
500 5 I500L, I500V,
504 5
499 7 P499S,
505 7 Q505R,
498 8
506 8
497 8 L497P,
507 8 R507Q, R507W,
496 9
508 9 E508G,
495 10 T495S, T495S, T495A,
509 10 H509Q, H509Q, H509R,
494 11
510 11 H510R, H510Y,
493 11 G493A,
511 11 R511Q, R511W,
492 12 L492ins,
512 12
491 13
513 13 T513A, T513S, T513S,
490 13
514 13 I514T,
489 14
515 14
488 14 D488E, D488E,
516 14
487 15 E487K,
517 15 I517T,