KCNH2 Variant G189Ins Detail

We estimate the penetrance of LQTS for KCNH2 G189Ins is 7%. This variant was found in a total of 2 carriers in 2 papers or gnomAD (version 4), 0 had LQTS. G189Ins is not present in gnomAD. G189Ins has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G189Ins around 7% (0/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 5
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
18452873 2008 1 1 LQT3
10790218 2000 1 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 2 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

G189Ins has 31 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
189 0 G189Ins,
188 4 A188X, A188P, A188S,
190 4 A190V, A190T,
187 5 G187A, G187X, G187Del, G187S,
191 5 P191fsX, P191Q,
186 7 G186fsX,
192 7 G192fsX,
185 8
193 8 A193X, A193V, A193fsX, A193T,
184 8 G184Del,
194 8 V194M,
183 9 G183fsX,
195 9
182 10 S182X,
196 10
181 11 R181Q, R181W, R181fsX,
197 11 D197Y, D197N,
180 11
198 11 V198L, V198L,
179 12 S179W,
199 12
178 13
200 13 L200Q,
177 13 E177X,
201 13
176 14 R176W, R176X, R176Q,
202 14
175 14 A175S, A175D, A175X,
203 14 A203T,
174 15
204 15