KCNQ1 Variant R174C Detail

We estimate the penetrance of LQTS for KCNQ1 R174C is 74%. This variant was found in a total of 4 carriers in 6 papers or gnomAD, 3 had LQTS. R174C is present in 1 alleles in gnomAD. R174C has been functionally characterized in 3 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R174C around 74% (10/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.38 1.0 4 0.98 79
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 2 None 2 None
30758498 2019 7 None 7 None
29037160 2017 2 None 1 None
19934648 2010 None None None None
19716085 2009 1 None 1 None
17192539 2006 4 None 4 None
LITERATURE, COHORT, AND GNOMAD: - 4 1 3
VARIANT FEATURES ALONE: - 10 3 7 -
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)
19934648 Oocytes 47 17.0 1.0 None
9312006 COS 0 None None None
30571187 HEK 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)
19934648 Oocytes None None None
9312006 COS 60 3.0 None 0.9
30571187 HEK None None None

R174C has 61 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
174 0 R174H, R174C, R174L,
114 4
170 5
173 5
115 6 E115A, E115G,
171 6
175 6 L175I,
177 7 S177F,
172 7 V172M, V172E,
111 7 Y111C,
243 8 R243H, R243C, R243P, R243S,
193 8 F193L, F193L, F193L,
110 8 V110I,
202 8 D202N, D202H,
199 8 S199A,
178 9 A178T, A178del,
168 9 G168R, G168R, G168R, G168R,
176 9
113 9
169 9 T169M, T169R,
198 10 I198V, I198T,
167 10
126 10 H126D,
240 10 H240R, H240P,
112 10
125 10
194 10 A194P, A194T,
244 11
166 11 F166V,
107 11 Q107H, Q107H,
196 11
190 11 R190W, R190Q, R190L,
117 11 P117L,
203 11 L203P,
108 11 G108S,
116 11
184 12 Y184S, Y184C, Y184D, Y184H,
180 12
179 12 G179S,
241 12 V241F, V241I, V241G,
181 12 R181C,
122 12 C122Y,
129 12 V129I,
201 12 I201del,
200 12
206 13 V206L,
242 13 D242N, D242Y,
197 13 P197L,
205 14 V205M,
189 14 G189R, G189R, G189E,
165 14 V165M,
106 14
164 14
245 14 G245V,
109 14 R109C, R109L,
191 14
237 15
239 15
204 15 I204M, I204F,
183 15 K183R,
163 15