KCNH2 Variant T777P Detail

We estimate the penetrance of LQTS for KCNH2 T777P is 26%. We are unaware of any observations of this variant in individuals. T777P is not present in gnomAD. T777P 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 T777P around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.269 0.36 -1 0.851 32
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.

T777P has 57 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
777 0
778 4 A778T,
776 5 L776I, L776P,
834 5 H834R,
835 5 R835W, R835fsX, R835Q,
775 6
833 8
836 8
779 8
815 8
816 8 G816V,
832 8
780 9
774 9 D774X, D774Y,
807 9 E807X,
837 9 D837G, D837N, D837Y,
806 10 G806R, G806R,
722 10
770 10
809 10
838 11 L838R,
818 11 S818A, S818L, S818W,
844 11 M844V,
817 11
805 11 F805S, F805C,
769 12
839 12
862 12 L862P,
759 12 K759N, K759N,
773 12
808 12
813 13
771 13 H771R, H771fsX,
723 13 C723X, C723G, C723R,
814 13
757 13
758 13
812 13 Y812S,
753 13 A753S,
781 13
749 13
772 14
761 14
845 14
840 14 E840Q,
822 14 V822L, V822M, V822L,
820 14 G820R, G820R,
840 14 E840Q,
861 14 N861I, N861H,
841 14 V841L, V841L,
721 14 P721L,
752 14 R752Q, R752W, R752P,
756 14 M756V,
804 14
831 15
830 15
858 15 I858T, I858V,