KCNQ1 Variant R181H Detail

We estimate the penetrance of LQTS for KCNQ1 R181H is 36%. We are unaware of any observations of this variant in individuals. R181H is not present in gnomAD. R181H 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R181H around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.44 1.0 0 0.841 49
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
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)
34930020 HEK 111 6.93 1.21 0.87

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)
34930020 HEK 104 7.39 0.96 0.95

R181H has 42 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
181 0 R181C,
184 5 Y184S, Y184C, Y184D, Y184H,
180 5
183 5 K183R,
182 5
178 6 A178T, A178del,
111 6 Y111C,
179 7 G179S,
177 8 S177F,
193 8 F193L, F193L, F193L,
116 9
185 9 V185L, V185L, V185M, V185del,
108 9 G108S,
189 9 G189R, G189R, G189E,
115 9 E115A, E115G,
112 9
190 10 R190W, R190Q, R190L,
244 11
192 11 R192C, R192H,
186 11 G186R, G186D,
107 11 Q107H, Q107H,
196 12
188 12 W188C, W188C, W188G, W188S,
110 12 V110I,
175 12 L175I,
174 12 R174H, R174C, R174L,
114 12
194 13 A194P, A194T,
105 13
117 14 P117L,
191 14
176 14
243 14 R243H, R243C, R243P, R243S,
109 14 R109C, R109L,
106 14
199 14 S199A,
173 14
195 15 R195Q, R195W,
104 15 T104A, T104I,
187 15 L187P, L187F,
113 15
198 15 I198V, I198T,