KCNQ1 Variant L187F Detail

We estimate the penetrance of LQTS for KCNQ1 L187F is 24%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. L187F is present in 1 alleles in gnomAD. L187F has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L187F around 24% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.75 0.0 0 0.522 30
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 LQT1 Other Disease
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.

L187F has 24 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. This results from the fact that the functional KV7.1 channel 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 L187P, L187F,
186 5 G186R, G186D,
191 5
190 6 R190W, R190Q, R190L,
189 6 G189R, G189R, G189E,
188 6 W188C, W188C, W188G, W188S,
185 8 V185L, V185L, V185M, V185del,
192 9 R192C, R192H,
175 10 L175I,
194 10 A194P, A194T,
184 10 Y184S, Y184C, Y184D, Y184H,
193 11 F193L, F193L, F193L,
195 11 R195Q, R195W,
178 11 A178T, A178del,
179 11 G179S,
176 13
183 13 K183R,
182 13
177 14 S177F,
172 14 V172M, V172E,
171 14
181 15 R181C,
180 15
199 15 S199A,