KCNH2 Variant F805C Detail

We estimate the penetrance of LQTS for KCNH2 F805C is 76%. This variant was found in a total of 9 carriers in 4 papers or gnomAD, 7 had LQTS. F805C is not present in gnomAD. F805C has been functionally characterized in 5 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F805C around 76% (14/19).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.381 1.0 -3 0.978 76
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
11854117 2002 11 0 11
11844290 2002 7 2 5
10973849 2000 1 0 1
15840476 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 9 2 7 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
11741928 HEK293 0 None None None None
12837749 HEK293 19 None None None None
15851652 HEK293 None None None None
15961404 HEK293 0 None None None None
16432067 HEK293 5 None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
11741928 HEK293 None None None
12837749 HEK293 None None None
15851652 HEK293 None None None
15961404 HEK293 None None None
16432067 HEK293 60 None None None

F805C has 81 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
805 0 F805C, F805S,
780 4
806 5 G806R, G806R,
804 5
779 6
859 7 T859M, T859R,
860 7
781 7
799 7 L799sp,
782 7 I782fsX, I782N,
803 7 D803Y, D803X,
858 8 I858V, I858T,
862 8 L862P,
778 8 A778T,
787 8
822 8 V822M, V822L, V822L,
789 9
770 9
769 9
830 9
776 9 L776I, L776P,
807 9 E807X,
861 9 N861I, N861H,
832 10
800 10
797 10 A797T,
831 10
833 10
820 11 G820R, G820R,
808 11
777 11
818 11 S818W, S818L, S818A,
788 11 E788D, E788D, E788K,
802 12
761 12
798 12 I798fsX,
819 12 N819K, N819K,
783 12 S783P,
821 12 D821E, D821E,
828 12
56 12 R56Q,
786 12
824 12
856 12
857 12 E857X,
57 12 A57P,
60 13 M60T,
785 13 G785D, G785S, G785fsX,
790 13
763 13
796 13 V796L, V796Del, V796L,
823 13 R823W, R823fsX, R823Q, R823T,
834 13 H834R,
768 13
771 13 H771fsX, H771R,
801 13 K801T,
774 13 D774X, D774Y,
829 13 D829A, D829E, D829E,
736 13
816 13 G816V,
809 13
758 13
835 14 R835fsX, R835W, R835Q,
61 14 Q61R,
759 14 K759N, K759N,
772 14
775 14
740 14 C740W, C740G,
767 14 D767X,
42 14 I42N,
760 14
825 14
838 15 L838R,
853 15 W853X,
791 15 R791W, R791Q,
44 15 C44F, C44W, C44X,
773 15
863 15 R863X, R863P,
43 15 Y43D, Y43C,
762 15
723 15 C723X, C723R, C723G,