KCNH2 Variant A190T Detail

We estimate the penetrance of LQTS for KCNH2 A190T is 1%. This variant was found in a total of 152 carriers in 4 papers or gnomAD (version 4), 1 had LQTS. A190T is present in 150 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 133% of WT with a standard error of 12%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. A190T 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 A190T around 1% (1/162).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.081 0.414 0 0.415 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
Italy Cohort 2020 1 0 1
14661677 2003 1 1
15913580 2005 1 0
29752375 2018 2 0 SIDS
LITERATURE, COHORT, AND GNOMAD: - 152 35 1 -
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.

A190T 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
190 0 A190V, A190T,
189 4 G189Ins,
191 4 P191fsX, P191Q,
188 5 A188P, A188X, A188S,
192 5 G192fsX,
187 7 G187A, G187S, G187Del, G187X,
193 7 A193T, A193X, A193V, A193fsX,
186 8 G186fsX,
194 8 V194M,
185 8
195 8
184 9 G184Del,
196 9
183 10 G183fsX,
197 10 D197N, D197Y,
182 11 S182X,
198 11 V198L, V198L,
181 11 R181W, R181Q, R181fsX,
199 11
180 12
200 12 L200Q,
179 13 S179W,
201 13
178 13
202 13
177 14 E177X,
203 14 A203T,
176 14 R176W, R176X, R176Q,
204 14
175 15 A175X, A175S, A175D,
205 15 P205L,