KCNH2 Variant Y700D Detail

We estimate the penetrance of LQTS for KCNH2 Y700D is 21%. We are unaware of any observations of this variant in individuals. Y700D is not present in gnomAD. Y700D 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 Y700D around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.504 1.0 -3 0.964 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.

Y700D has 65 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
700 0
704 6 A704T, A704V,
703 6
720 6
701 6
699 6 E699D, E699D,
697 7 L697X,
721 7 P721L,
724 8 L724X,
764 8
719 8
702 8
696 8 R696H, R696C,
767 9 D767X,
763 9
698 9 E698K, E698X,
762 9
706 10 S706C, S706F,
723 10 C723G, C723X, C723R,
707 10
705 11 W705fsX, W705X,
765 11
708 11
761 11
766 11
725 11 Q725R, Q725fsX,
693 11 L693X,
695 11
680 11
768 12
827 12
717 12 L717P,
716 12 V716G,
7 12
769 12
4 12
677 12 M677T,
6 12 G6R,
676 12 Q676X, Q676fsX,
722 12
727 12
728 12
710 13
673 13
694 13 R694H, R694C,
718 13
5 13
824 13
828 13
760 13
726 13
709 14
830 14
683 14
481 14
711 14 I711V,
829 14 D829E, D829E, D829A,
692 14
713 15 M713V,
715 15 A715A, A715T, A715sp, A715V,
684 15
712 15 D712N,
826 15 T826A, T826I,
679 15 R679Q, R679W,
478 15 A478D,