KCNH2 Variant Q725R Detail

We estimate the penetrance of LQTS for KCNH2 Q725R is 12%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. Q725R is present in 1 alleles in gnomAD. Q725R 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Q725R around 12% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.891 0.947 1 0.902 17
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: - 1 1 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.

Q725R has 50 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
725 0 Q725R, Q725fsX,
717 5 L717P,
726 5
721 5 P721L,
722 5
724 6 L724X,
756 6 M756V,
720 6
728 6
723 7 C723G, C723X, C723R,
729 7
719 8
727 8
718 8
752 9 R752P, R752W, R752Q,
716 9 V716G,
755 9
714 10
730 10
697 10 L697X,
715 11 A715A, A715T, A715sp, A715V,
753 11 A753S,
700 11
732 11
757 11
693 11 L693X,
696 12 R696H, R696C,
683 12
713 12 M713V,
768 12
731 12 H731R,
733 13
769 13
754 13
758 13
771 13 H771R, H771fsX,
759 13 K759N, K759N,
687 13
749 14
767 14 D767X,
751 14 L751V,
680 14
770 14
689 14
701 14
774 14 D774Y, D774X,
760 14
761 15
684 15
712 15 D712N,