KCNQ1 Variant A152V Detail

We estimate the penetrance of LQTS for KCNQ1 A152V is 46%. We are unaware of any observations of this variant in individuals. A152V is not present in gnomAD. A152V 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A152V around 46% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.33 0.907 0 0.883 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 6 4 -
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.

A152V 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
152 0
153 4 T153M,
155 5
149 5
151 5
154 5
156 5
150 6 A150T,
143 6 S143F, S143P, S143Y,
139 7
142 8
148 8
140 9 S140G, S140R, S140R, S140R,
159 9 M159del,
157 9 F157C,
144 10 T144A,
145 10
146 10 E146K, E146G, E146Q,
136 10
141 10 V141M,
147 10 Q147R,
160 11 E160del, E160K, E160V,
158 11
138 11
135 12
231 12 R231C, R231H, R231S,
217 12
230 12
137 13 L137F, L137P,
234 13 Q234H, Q234H,
227 13
226 13 A226V,
161 13
222 14
213 14
163 15
162 15 V162M,
216 15 G216R,