KCNQ1 Variant F193L Detail

We estimate the penetrance of LQTS for KCNQ1 F193L is 54%. This variant was found in a total of 5 carriers in 3 papers or gnomAD, 3 had LQTS. F193L is not present in gnomAD. F193L has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F193L around 54% (8/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.53 1.0 -3 0.912 64
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
30758498 2019 4 None None None
12808265 2003 1 None 1 None
12653681 2003 4 2 2 None
LITERATURE, COHORT, AND GNOMAD: - 5 2 3
VARIANT FEATURES ALONE: - 10 5 5 -
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

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation 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 Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
12653681 Oocytes 80 0.0 1.833 None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
12653681 Oocytes None None None

F193L has 48 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
193 0 F193L, F193L, F193L,
194 5 A194P, A194T,
184 5 Y184S, Y184C, Y184D, Y184H,
178 6 A178T, A178del,
175 6 L175I,
196 6
190 6 R190W, R190Q, R190L,
189 7 G189R, G189R, G189E,
199 7 S199A,
191 8
192 8 R192C, R192H,
174 8 R174H, R174C, R174L,
183 8 K183R,
177 8 S177F,
195 8 R195Q, R195W,
171 8
181 8 R181C,
111 9 Y111C,
115 9 E115A, E115G,
198 9 I198V, I198T,
179 9 G179S,
200 10
197 10 P197L,
186 10 G186R, G186D,
244 10
185 10 V185L, V185L, V185M, V185del,
188 10 W188C, W188C, W188G, W188S,
202 11 D202N, D202H,
180 11
187 11 L187P, L187F,
172 11 V172M, V172E,
173 11
176 11
243 11 R243H, R243C, R243P, R243S,
114 11
203 11 L203P,
182 11
201 12 I201del,
170 13
116 13
110 13 V110I,
107 13 Q107H, Q107H,
112 13
108 14 G108S,
168 14 G168R, G168R, G168R, G168R,
245 14 G245V,
240 14 H240R, H240P,
204 15 I204M, I204F,