KCNH2 Variant L200Q Detail

We estimate the penetrance of LQTS for KCNH2 L200Q is 6%. This variant was found in a total of 3 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. L200Q is present in 3 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 138% of WT with a standard error of 1%; 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. L200Q 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 L200Q around 6% (0/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.421 0.968 0 0.513 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
LITERATURE, COHORT, AND GNOMAD: - 3 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.

L200Q 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
200 0 L200Q,
199 4
201 4
198 5 V198L, V198L,
202 5
197 7 D197Y, D197N,
203 7 A203T,
196 8
204 8
195 8
205 8 P205L,
194 9 V194M,
206 9
193 10 A193X, A193V, A193fsX, A193T,
207 10 S207X,
192 11 G192fsX,
208 11 E208X,
191 11 P191fsX, P191Q,
209 11
190 12 A190V, A190T,
210 12
189 13 G189Ins,
211 13
188 13 A188X, A188P, A188S,
212 13
187 14 G187A, G187X, G187Del, G187S,
213 14 D213G,
186 14 G186fsX,
214 14 E214X,
185 15
215 15 V215X, V215G,