KCNQ1 Variant A149G Detail

We estimate the penetrance of LQTS for KCNQ1 A149G is 39%. We are unaware of any observations of this variant in individuals. A149G is not present in gnomAD. A149G 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A149G around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.41 0.094 -1 0.663 48
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
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.

A149G has 32 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
149 0
150 4 A150T,
152 5
153 5 T153M,
143 5 S143F, S143P, S143Y,
151 6
146 6 E146K, E146G, E146Q,
148 6
147 7 Q147R,
145 8
142 8
144 8 T144A,
154 8
155 9
156 9
140 10 S140G, S140R, S140R, S140R,
139 10
141 11 V141M,
157 12 F157C,
227 12
231 12 R231C, R231H, R231S,
217 13
298 13 S298I, S298N,
138 13
222 14
159 14 M159del,
136 14
226 14 A226V,
297 14 G297S, G297D, G297R,
230 14
160 14 E160del, E160K, E160V,
299 15