KCNH2 Variant L697P Detail

We estimate the penetrance of LQTS for KCNH2 L697P is 22%. We are unaware of any observations of this variant in individuals. L697P is not present in gnomAD. L697P has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L697P around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.716 1.0 -3 0.962 21
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 8 2 -
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.

L697P has 62 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
697 0 L697X,
698 5 E698X, E698K,
693 6 L693X,
696 6 R696C, R696H,
720 7
694 7 R694C, R694H,
700 7
724 7 L724X,
699 7 E699D, E699D,
680 7
701 7
695 8
684 8
728 8
689 8
683 9
727 9
702 9
692 10
721 10 P721L,
716 10 V716G,
677 10 M677T,
690 10
719 10
717 10 L717P,
681 10 R681W,
725 10 Q725fsX, Q725R,
691 11
704 11 A704V, A704T,
5 11
723 11 C723R, C723G, C723X,
703 11
726 12
767 12 D767X,
731 12 H731R,
687 12
676 12 Q676fsX, Q676X,
7 12
764 13
729 13
6 13 G6R,
679 13 R679W, R679Q,
766 13
4 13
682 13 E682X,
678 13
685 13 R685P, R685C, R685H,
768 13
673 13
732 13
715 14 A715sp, A715A, A715T, A715V,
688 14
730 14
705 14 W705fsX, W705X,
718 14
713 14 M713V,
765 14
722 14
3 14
686 14
706 15 S706C, S706F,
763 15