KCNH2 Variant F683C Detail

We estimate the penetrance of LQTS for KCNH2 F683C is 30%. We are unaware of any observations of this variant in individuals. F683C is not present in gnomAD. F683C 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 F683C around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.773 1.0 -3 0.967 31
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.

F683C 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
683 0
684 5
687 5
680 6
686 6
713 6 M713V,
716 6 V716G,
682 7 E682X,
689 8
711 8 I711V,
717 8 L717P,
728 8
679 8 R679Q, R679W,
697 9 L697X,
685 9 R685H, R685P, R685C,
681 9 R681W,
715 10 A715A, A715T, A715sp, A715V,
732 10
688 10
720 10
712 10 D712N,
708 10
694 10 R694H, R694C,
714 10
731 10 H731R,
678 10
709 10
693 11 L693X,
677 11 M677T,
729 11
710 11
676 11 Q676fsX, Q676X,
707 11
698 11 E698X, E698K,
690 12
725 12 Q725R, Q725fsX,
719 12
701 12
724 12 L724X,
718 12
727 12
760 13
726 13
675 14
696 14 R696C, R696H,
700 14
721 14 P721L,
733 14
730 14
691 14
734 14 R734H, R734C,
692 15
695 15
706 15 S706F, S706C,
704 15 A704T, A704V,
705 15 W705fsX, W705X,