KCNH2 Variant I30Del Detail

We estimate the penetrance of LQTS for KCNH2 I30Del is 81%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. I30Del is not present in gnomAD. I30Del 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I30Del around 81% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 88
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
24606995 2014 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
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.

I30Del has 78 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
30 0 I30Del, I30T,
127 5
31 5 I31S,
29 5 F29L, F29L, F29V, F29S, F29L,
43 6 Y43C, Y43D,
41 7 V41A,
126 7
44 7 C44X, C44F, C44W,
48 7
32 7 A32T,
129 7 F129C,
45 8 N45K, N45D, N45K,
64 8 C64Y, C64R,
128 8 N128S,
42 8 I42N,
59 9
125 9
28 9 K28E,
66 9 C66R, C66Y, C66G,
60 10 M60T,
40 10
112 10 V112M,
47 10 G47C, G47V,
27 10 R27P, R27X,
124 10 M124R, M124T,
798 10 I798fsX,
19 10 I19F,
110 11 V110A,
111 11 D111V,
22 11 F22Y, F22S,
49 11 C49G, C49R,
56 11 R56Q,
113 11 V113Del,
65 11 T65P,
63 11 P63H,
39 11 C39X, C39R,
33 11 N33T,
18 11 I18M,
52 12 C52W,
51 12
69 12 L69Del, L69P,
15 12 L15V,
62 12 R62Q,
46 12 D46E, D46Y, D46E,
797 12 A797T,
114 12 P114S,
68 12 F68L, F68L, F68V, F68L,
86 13 L86R,
796 13 V796L, V796Del, V796L,
98 13
82 13 I82dup, I82Del, I82Ins, I82T,
55 13 S55L,
61 13 Q61R,
115 13 V115M,
108 13 C108Y,
54 13 Y54N, Y54X,
130 13 E130K,
109 13 L109X, L109P, L109Q,
795 14 V795I,
34 14 A34T,
23 14
57 14 A57P,
50 14 E50X,
53 14 G53R, G53S,
58 14 E58K, E58D, E58D,
26 14 S26I,
799 14 L799sp,
123 14
25 14 Q25P,
67 14
85 14 A85P, A85V,
800 15
21 15
94 15 V94L, V94L, V94A,
36 15 V36X,
16 15 D16A,
14 15
38 15