KCNH2 Variant P721L Detail

We estimate the penetrance of LQTS for KCNH2 P721L is 75%. This variant was found in a total of 3 carriers in 2 papers or gnomAD, 3 had LQTS. P721L is not present in gnomAD. P721L 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P721L around 75% (9/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.728 0.999 -3 0.915 67
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
France Cohort 2020 2 0 2
15840476 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

P721L has 58 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
721 0 P721L,
724 5 L724X,
720 5
723 5 C723X, C723G, C723R,
725 5 Q725fsX, Q725R,
722 5
719 6
700 7
717 8 L717P,
726 8
769 9
718 9
761 10
728 10
697 10 L697X,
768 10
767 10 D767X,
727 10
696 10 R696H, R696C,
756 10 M756V,
716 11 V716G,
763 11
704 11 A704T, A704V,
752 11 R752Q, R752W, R752P,
764 11
729 12
701 12
832 12
762 12
770 12
693 12 L693X,
703 12
715 12 A715sp, A715V, A715T, A715A,
699 12 E699D, E699D,
759 12 K759N, K759N,
771 13 H771R, H771fsX,
760 13
766 13
714 13
830 13
755 14
780 14
730 14
683 14
753 14 A753S,
680 14
822 14 V822L, V822M, V822L,
777 14
707 14
698 14 E698X, E698K,
834 14 H834R,
778 14 A778T,
765 15
708 15
774 15 D774X, D774Y,
824 15
714 15
702 15