KCNH2 Variant V198L Detail

We estimate the penetrance of LQTS for KCNH2 V198L is 8%. This variant was found in a total of 2 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. V198L is present in 2 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 76% of WT with a standard error of 18%; 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. V198L has not been functionally characterized. This residue is located in a Mild_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 V198L around 8% (0/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.108 0.021 2 0.429 13
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: - 2 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.

V198L 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
198 0 V198L, V198L,
197 4 D197Y, D197N,
199 4
196 5
200 5 L200Q,
195 7
201 7
194 8 V194M,
202 8
193 8 A193X, A193V, A193fsX, A193T,
203 8 A203T,
192 9 G192fsX,
204 9
191 10 P191fsX, P191Q,
205 10 P205L,
190 11 A190V, A190T,
206 11
189 11 G189Ins,
207 11 S207X,
188 12 A188X, A188P, A188S,
208 12 E208X,
187 13 G187A, G187X, G187Del, G187S,
209 13
186 13 G186fsX,
210 13
185 14
211 14
184 14 G184Del,
212 14
183 15 G183fsX,
213 15 D213G,