KCNH2 Variant I42M Detail

We estimate the penetrance of LQTS for KCNH2 I42M is 68%. We are unaware of any observations of this variant in individuals. I42M is not present in gnomAD. I42M 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 I42M around 68% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.774 0.14 0 0.828 75
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.

I42M has 79 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
42 0 I42N,
41 5 V41A,
797 5 A797T,
31 5 I31S,
798 5 I798fsX,
796 5 V796Del, V796L, V796L,
32 6 A32T,
40 6
43 6 Y43D, Y43C,
795 6 V795I,
60 6 M60T,
33 7 N33T,
44 8 C44X, C44W, C44F,
30 8 I30T, I30Del,
788 8 E788D, E788K, E788D,
124 8 M124T, M124R,
61 8 Q61R,
789 8
799 9 L799sp,
15 9 L15V,
39 10 C39R, C39X,
59 10
860 10
794 10 V794I, V794D,
56 10 R56Q,
36 10 V36X,
125 10
64 10 C64Y, C64R,
790 10
29 11 F29L, F29L, F29S, F29V, F29L,
34 11 A34T,
126 11
859 11 T859R, T859M,
19 11 I19F,
63 11 P63H,
787 11
12 11 N12D,
62 11 R62Q,
127 11
800 11
45 12 N45D, N45K, N45K,
123 12
786 12
35 12 R35W,
791 12 R791W, R791Q,
57 12 A57P,
14 12
18 12 I18M,
16 13 D16A,
48 13
38 13
803 13 D803X, D803Y,
825 13
822 14 V822L, V822M, V822L,
115 14 V115M,
66 14 C66Y, C66R, C66G,
55 14 S55L,
823 14 R823T, R823fsX, R823Q, R823W,
13 14 T13N,
37 14
65 14 T65P,
820 14 G820R, G820R,
819 14 N819K, N819K,
58 14 E58D, E58D, E58K,
793 14 D793N,
792 14
805 14 F805S, F805C,
49 14 C49R, C49G,
824 15
122 15
17 15
821 15 D821E, D821E,
785 15 G785D, G785S, G785fsX,
46 15 D46E, D46E, D46Y,
22 15 F22Y, F22S,
114 15 P114S,
862 15 L862P,
861 15 N861I, N861H,
86 15 L86R,