KCNH2 Variant Y43D Detail

We estimate the penetrance of LQTS for KCNH2 Y43D is 69%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 2 had LQTS. Y43D is not present in gnomAD. Y43D has been functionally characterized in 1 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y43D around 69% (8/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.093 0.129 -4 0.906 67
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
Japan Cohort 2020 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 3 1 2 -
VARIANT FEATURES ALONE: - 10 4 6 -
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)
19419905 CHO 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)
19419905 CHO 6.6 None 0.457446809

Y43D has 80 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
43 0 Y43C, Y43D,
44 4 C44X, C44F, C44W,
798 5 I798fsX,
31 6 I31S,
45 6 N45D, N45K, N45K,
29 6 F29V, F29L, F29S, F29L, F29L,
42 6 I42N,
30 6 I30T, I30Del,
19 7 I19F,
56 7 R56Q,
799 8 L799sp,
41 8 V41A,
800 8
60 8 M60T,
797 8 A797T,
15 9 L15V,
46 9 D46Y, D46E, D46E,
48 9
32 9 A32T,
59 10
18 10 I18M,
786 10
16 10 D16A,
126 10
47 10 G47V, G47C,
788 10 E788D, E788K, E788D,
803 10 D803Y, D803X,
49 10 C49R, C49G,
22 10 F22S, F22Y,
127 11
796 11 V796Del, V796L, V796L,
801 11 K801T,
27 11 R27P, R27X,
23 11
787 11
859 11 T859R, T859M,
40 11
124 11 M124R, M124T,
795 11 V795I,
785 11 G785fsX, G785S, G785D,
28 12 K28E,
55 12 S55L,
789 12
57 12 A57P,
128 12 N128S,
17 12
860 12
33 12 N33T,
802 12
61 13 Q61R,
129 13 F129C,
14 13
20 13 R20G, R20L,
125 13
825 13
64 13 C64Y, C64R,
782 13 I782N, I782fsX,
21 13
12 13 N12D,
26 14 S26I,
50 14 E50X,
52 14 C52W,
62 14 R62Q,
13 14 T13N,
58 14 E58K, E58D, E58D,
804 14
25 14 Q25P,
24 14
39 14 C39X, C39R,
51 15
63 15 P63H,
826 15 T826A, T826I,
113 15 V113Del,
66 15 C66R, C66Y, C66G,
115 15 V115M,
54 15 Y54N, Y54X,
53 15 G53S, G53R,
805 15 F805C, F805S,
790 15
824 15