KCNQ1 Variant P499L Detail

We estimate the penetrance of LQTS for KCNQ1 P499L is 11%. We are unaware of any observations of this variant in individuals. P499L is not present in gnomAD. P499L 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P499L around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.98 0.774 -3 0.826 0
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 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.

P499L 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
499 0 P499S,
498 4
500 4 I500L, I500V,
497 5 L497P,
501 5 T501A,
496 7
502 7
495 8 T495S, T495S, T495A,
503 8
494 8
504 8
493 9 G493A,
505 9 Q505R,
492 10 L492ins,
506 10
491 11
507 11 R507Q, R507W,
490 11
508 11 E508G,
489 12
509 12 H509Q, H509Q, H509R,
488 13 D488E, D488E,
510 13 H510R, H510Y,
487 13 E487K,
511 13 R511Q, R511W,
486 14 A486T,
512 14
485 14 F485S,
513 14 T513A, T513S, T513S,
484 15
514 15 I514T,