KCNH2 Variant I82T Detail

We estimate the penetrance of LQTS for KCNH2 I82T is 70%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. I82T is not present in gnomAD. I82T 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 I82T around 70% (8/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.247 0.03 -1 0.787 70
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
23899126 2013 2 0 2 seizures
LITERATURE, COHORT, AND GNOMAD: - 2 0 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.

I82T has 53 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
82 0 I82dup, I82Del, I82T, I82Ins,
83 4 A83fsX, A83P,
79 5 A79Del, A79fsX, A79S, A79T,
81 5 Q81X, Q81E, Q81H, Q81P, Q81H,
80 6 A80P,
85 6 A85V, A85P,
94 6 V94L, V94A, V94L,
65 7 T65P,
78 7 A78P, A78T,
84 7
86 7 L86R,
110 7 V110A,
112 8 V112M,
92 8 R92C, R92L,
64 8 C64R, C64Y,
96 9 I96T, I96V,
66 9 C66G, C66Y, C66R,
77 9 R77S,
127 9
87 10 L87P,
70 10 H70Q, H70R, H70Q,
76 10
111 11 D111V,
125 11
98 11
95 11 E95K, E95G,
90 11 E90K,
93 11 K93X, K93R,
88 11
67 11
109 11 L109P, L109X, L109Q,
75 11 Q75X,
63 12 P63H,
129 12 F129C,
69 12 L69P, L69Del,
74 12 T74M, T74fsX,
108 12 C108Y,
89 12 A89V, A89G,
39 12 C39R, C39X,
113 12 V113Del,
97 12
91 12
114 12 P114S,
30 13 I30T, I30Del,
126 13
128 13 N128S,
32 13 A32T,
68 14 F68V, F68L, F68L, F68L,
71 14 G71E, G71R, G71R, G71W,
38 14
41 15 V41A,
40 15
107 15 L107P,