KCNQ1 Variant P117L Detail

We estimate the penetrance of LQTS for KCNQ1 P117L is 86%. This variant was found in a total of 2 carriers in 6 papers or gnomAD, 2 had LQTS. P117L is not present in gnomAD. P117L 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P117L around 86% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.81 0.998 -2 0.926 95
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
32893267 2020 1 None 1 None
30758498 2019 5 None 5 None
19716085 2009 1 None 1 None
19114714 2009 None None None None
17192539 2006 1 None 1 None
17053194 2006 None None None None
LITERATURE, COHORT, AND GNOMAD: - 2 0 2
VARIANT FEATURES ALONE: - 10 2 8 -
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)
17053194 COS 0 None None 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)
17053194 COS 50 None None 0.51

P117L has 40 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
117 0 P117L,
118 5
122 6 C122Y,
116 6
119 6 G119R, G119V,
112 6
113 7
115 7 E115A, E115G,
126 7 H126D,
114 7
123 8
243 9 R243H, R243C, R243P, R243S,
111 9 Y111C,
244 9
125 10
121 10
120 10 W120C, W120C,
110 10 V110I,
241 11 V241F, V241I, V241G,
124 11
174 11 R174H, R174C, R174L,
242 11 D242N, D242Y,
108 11 G108S,
246 11
245 12 G245V,
127 12 F127L, F127L, F127L,
109 12 R109C, R109L,
177 13 S177F,
129 13 V129I,
170 13
181 14 R181C,
247 14 T247I,
128 14 A128del,
180 14
198 14 I198V, I198T,
130 14
240 14 H240R, H240P,
173 14
178 15 A178T, A178del,
107 15 Q107H, Q107H,