KCNQ1 Variant G168R Detail

We estimate the penetrance of LQTS for KCNQ1 G168R is 70%. This variant was found in a total of 56 carriers in 22 papers or gnomAD, 44 had LQTS. G168R is present in 3 alleles in gnomAD. G168R has been functionally characterized in 2 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G168R around 70% (46/66).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.38 1.0 -3 0.937 43
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 10 None 10 None
31484877 2019 2 1 1 None
30758498 2019 8 None 8 None
27921062 2016 1 None 1 Duodenal ampullary adenoma
27041150 2016 2 2 None None
26496715 2016 2 None 2 None
24667783 2015 2 1 1 None
24363352 2014 1 None None None
23631430 2013 6 None None None
23153844 2012 87 None 1 None
22949429 2012 3 None 3 None
22949429 2012 1 None 1 None
21956039 2011 5 None 5 None
21131640 2011 1 1 None AF
19841300 2009 3 None 3 None
19716085 2009 15 None 15 None
19716085 2009 4 None 4 None
19490272 2009 66 None 66 None
17470695 2007 44 None 44 None
17192539 2006 1 None 1 None
14678125 2003 37 None 37 None
12566525 2003 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 56 12 44
VARIANT FEATURES ALONE: - 10 8 2 -
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)
15051636 Oocytes 5 None None None
22456477 HEK 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)
15051636 Oocytes 30 None None None
22456477 HEK 20 None None None

G168R has 49 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
168 0 G168R, G168R, G168R, G168R,
169 4 T169M, T169R,
171 6
167 6
170 6
165 6 V165M,
172 6 V172M, V172E,
166 6 F166V,
206 6 V206L,
164 7
173 8
203 9 L203P,
202 9 D202N, D202H,
174 9 R174H, R174C, R174L,
163 9
175 10 L175I,
205 10 V205M,
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
162 10 V162M,
210 11 M210I, M210I, M210I,
176 11
209 11 S209P,
199 11 S199A,
240 11 H240R, H240P,
161 12
237 12
114 12
204 12 I204M, I204F,
208 12 A208V,
160 13 E160del, E160K, E160V,
129 13 V129I,
201 13 I201del,
125 13
194 13 A194P, A194T,
177 14 S177F,
200 14
198 14 I198V, I198T,
193 14 F193L, F193L, F193L,
233 14 L233P,
213 14
243 14 R243H, R243C, R243P, R243S,
115 14 E115A, E115G,
126 14 H126D,
110 15 V110I,
211 15
132 15 I132L,
159 15 M159del,
190 15 R190W, R190Q, R190L,
133 15 V133I,