KCNH2 Variant A704V Detail

We estimate the penetrance of LQTS for KCNH2 A704V is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. A704V is present in 1 alleles in gnomAD. A704V has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A704V around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.744 0.63 0 0.842 7
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 10 0 -
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.

A704V has 56 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
704 0 A704T, A704V,
703 4
706 5 S706F, S706C,
708 5
700 6
707 6
705 6 W705fsX, W705X,
701 6
702 7
710 8
709 8
762 8
719 9
711 9 I711V,
699 10 E699D, E699D,
764 10
720 10
673 10
686 11
763 11
713 11 M713V,
676 11 Q676fsX, Q676X,
721 11 P721L,
697 11 L697X,
4 11
827 11
712 11 D712N,
761 11
698 12 E698X, E698K,
677 12 M677T,
760 12
672 12 R672H, R672C,
669 13 G669C, G669R, G669X,
767 13 D767X,
724 13 L724X,
765 13
478 13 A478D,
680 13
829 13 D829A, D829E, D829E,
696 14 R696C, R696H,
716 14 V716G,
6 14 G6R,
687 14
828 14
682 14 E682X,
714 14
670 14
830 14
479 15
718 15
674 15 H674Y, H674fsX,
481 15
766 15
723 15 C723X, C723R, C723G,
717 15 L717P,
683 15