KCNH2 Variant Y43N Detail

We estimate the penetrance of LQTS for KCNH2 Y43N is 69%. We are unaware of any observations of this variant in individuals. Y43N is not present in gnomAD. Y43N has not been functionally characterized. 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 Y43N around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.523 0.129 -4 0.892 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
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.

Y43N 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 Y43D, Y43C,
44 4 C44X, C44W, C44F,
798 5 I798fsX,
31 6 I31S,
45 6 N45K, N45D, N45K,
29 6 F29L, F29L, F29V, F29S, 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 D46E, D46E, D46Y,
48 9
32 9 A32T,
59 10
18 10 I18M,
786 10
16 10 D16A,
126 10
47 10 G47C, G47V,
788 10 E788D, E788D, E788K,
803 10 D803Y, D803X,
49 10 C49R, C49G,
22 10 F22S, F22Y,
127 11
796 11 V796L, V796L, V796Del,
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 R20L, R20G,
125 13
825 13
64 13 C64R, C64Y,
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 E58D, E58D, E58K,
804 14
25 14 Q25P,
24 14
39 14 C39R, C39X,
51 15
63 15 P63H,
826 15 T826I, T826A,
113 15 V113Del,
66 15 C66G, C66R, C66Y,
115 15 V115M,
54 15 Y54X, Y54N,
53 15 G53S, G53R,
805 15 F805S, F805C,
790 15
824 15