KCNQ1 Variant R195Q Detail

We estimate the penetrance of LQTS for KCNQ1 R195Q is 11%. This variant was found in a total of 12 carriers in 3 papers or gnomAD, 0 had LQTS. R195Q is present in 11 alleles in gnomAD. R195Q 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R195Q around 11% (2/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.42 0.998 1 0.926 20
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 3 None 3 None
22949429 2012 1 1 None None
19841300 2009 1 1 None 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 49 -0.2 None 0.887373677

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

R195Q 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
195 0 R195Q, R195W,
194 5 A194P, A194T,
191 6
192 6 R192C, R192H,
196 8
189 8 G189R, G189R, G189E,
193 8 F193L, F193L, F193L,
200 8
197 9 P197L,
199 9 S199A,
184 10 Y184S, Y184C, Y184D, Y184H,
188 10 W188C, W188C, W188G, W188S,
187 11 L187P, L187F,
190 11 R190W, R190Q, R190L,
183 11 K183R,
198 12 I198V, I198T,
203 12 L203P,
175 12 L175I,
186 13 G186R, G186D,
201 13 I201del,
171 13
178 13 A178T, A178del,
185 13 V185L, V185L, V185M, V185del,
202 14 D202N, D202H,
204 14 I204M, I204F,
181 15 R181C,