KCNQ1 Variant R192C Detail

We estimate the penetrance of LQTS for KCNQ1 R192C is 27%. This variant was found in a total of 14 carriers in 2 papers or gnomAD, 3 had LQTS. R192C is present in 11 alleles in gnomAD. R192C has been functionally characterized in 1 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R192C around 27% (6/24).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.81 1.0 -3 0.94 36
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
26496715 2016 3 None 3 None
23631430 2013 1 None None None
LITERATURE, COHORT, AND GNOMAD: - 14 11 3
VARIANT FEATURES ALONE: - 10 7 3 -
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 21 3.2 None 0.0

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

R192C has 26 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
192 0 R192C, R192H,
189 5 G189R, G189R, G189E,
188 6 W188C, W188C, W188G, W188S,
195 6 R195Q, R195W,
191 6
183 6 K183R,
184 7 Y184S, Y184C, Y184D, Y184H,
193 8 F193L, F193L, F193L,
194 8 A194P, A194T,
185 9 V185L, V185L, V185M, V185del,
187 9 L187P, L187F,
186 9 G186R, G186D,
190 9 R190W, R190Q, R190L,
196 10
182 10
181 11 R181C,
178 11 A178T, A178del,
179 12 G179S,
199 12 S199A,
197 12 P197L,
175 13 L175I,
200 13
180 14
177 14 S177F,
198 15 I198V, I198T,
111 15 Y111C,