KCNQ1 Variant R192H Detail

We estimate the penetrance of LQTS for KCNQ1 R192H is 30%. This variant was found in a total of 4 carriers in 1 papers or gnomAD, 1 had LQTS. R192H is present in 3 alleles in gnomAD. R192H has not been functionally characterized. 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 R192H around 30% (4/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.23 0.997 3 0.943 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
16922724 2006 1 None 1 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.

R192H 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,