KCNH2 Variant G187S Detail

We estimate the penetrance of LQTS for KCNH2 G187S is 8%. This variant was found in a total of 1 carriers in 1 papers or gnomAD (version 4), 0 had LQTS. G187S is not present in gnomAD. We have tested the trafficking efficiency of this variant, 138% of WT with a standard error of 33%; 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. G187S has been functionally characterized in 1 papers. 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 G187S around 8% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.481 0.002 1 0.307 7
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
14661677 2003 1 1
LITERATURE, COHORT, AND GNOMAD: - 1 1 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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
31493593 HEK293 100 100 0.0 0.0 None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
31493593 HEK293 100 100 None None None

G187S 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
187 0 G187A, G187X, G187Del, G187S,
186 4 G186fsX,
188 4 A188X, A188P, A188S,
185 5
189 5 G189Ins,
184 7 G184Del,
190 7 A190V, A190T,
183 8 G183fsX,
191 8 P191fsX, P191Q,
182 8 S182X,
192 8 G192fsX,
181 9 R181Q, R181W, R181fsX,
193 9 A193X, A193V, A193fsX, A193T,
180 10
194 10 V194M,
179 11 S179W,
195 11
178 11
196 11
177 12 E177X,
197 12 D197Y, D197N,
176 13 R176W, R176X, R176Q,
198 13 V198L, V198L,
175 13 A175S, A175D, A175X,
199 13
174 14
200 14 L200Q,
173 14
201 14
172 15 A172V,
202 15