KCNQ1 Variant P197L Detail

We estimate the penetrance of LQTS for KCNQ1 P197L is 12%. This variant was found in a total of 14 carriers in 1 papers or gnomAD, 1 had LQTS. P197L is present in 13 alleles in gnomAD. P197L has been functionally characterized in 2 papers. 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P197L around 12% (2/24).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.22 0.998 0 0.965 31
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
29197658 2018 1 None 1 None
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)
30571187 HEK -5 None None None
30571187 HEK 147 0.9 None 0.837047848

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)
30571187 HEK None None None
30571187 HEK None None None

P197L has 36 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
197 0 P197L,
196 4
198 5 I198V, I198T,
200 5
199 6 S199A,
201 6 I201del,
194 8 A194P, A194T,
195 9 R195Q, R195W,
202 9 D202N, D202H,
245 9 G245V,
248 10 W248C, W248C, W248R, W248R,
193 10 F193L, F193L, F193L,
244 10
243 10 R243H, R243C, R243P, R243S,
204 10 I204M, I204F,
239 11
203 11 L203P,
240 11 H240R, H240P,
242 11 D242N, D242Y,
249 11 R249S, R249S,
171 12
236 12 L236Q, L236R,
192 12 R192C, R192H,
246 12
115 13 E115A, E115G,
205 13 V205M,
191 13
184 13 Y184S, Y184C, Y184D, Y184H,
174 13 R174H, R174C, R174L,
247 14 T247I,
241 14 V241F, V241I, V241G,
183 14 K183R,
175 14 L175I,
189 14 G189R, G189R, G189E,
252 15 G252R,
206 15 V206L,