KCNQ1 Variant R190L Detail

We estimate the penetrance of LQTS for KCNQ1 R190L is 46%. This variant was found in a total of 4 carriers in 4 papers or gnomAD, 1 had LQTS. R190L is present in 1 alleles in gnomAD. R190L has not been functionally characterized. 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R190L around 46% (6/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.45 1.0 -1 0.953 57
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 1 None 1 None
20138589 2010 2 2 None None
19716085 2009 1 None 1 None
17192539 2006 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 4 3 1
VARIANT FEATURES ALONE: - 10 5 5 -
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.

R190L has 38 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
190 0 R190W, R190Q, R190L,
186 5 G186R, G186D,
189 5 G189R, G189R, G189E,
175 5 L175I,
178 5 A178T, A178del,
187 6 L187P, L187F,
193 6 F193L, F193L, F193L,
191 7
185 7 V185L, V185L, V185M, V185del,
184 7 Y184S, Y184C, Y184D, Y184H,
179 7 G179S,
188 8 W188C, W188C, W188G, W188S,
177 8 S177F,
176 8
194 8 A194P, A194T,
192 9 R192C, R192H,
172 10 V172M, V172E,
180 10
181 10 R181C,
183 10 K183R,
171 10
173 11
182 11
174 11 R174H, R174C, R174L,
195 11 R195Q, R195W,
111 11 Y111C,
107 11 Q107H, Q107H,
199 12 S199A,
196 12
115 13 E115A, E115G,
110 13 V110I,
108 13 G108S,
114 14
203 14 L203P,
200 14
170 15
168 15 G168R, G168R, G168R, G168R,
202 15 D202N, D202H,