KCNQ1 Variant I138V Detail

We estimate the penetrance of LQTS for KCNQ1 I138V is 33%. We are unaware of any observations of this variant in individuals. I138V is not present in gnomAD. I138V 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 I138V around 33% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.69 0.435 3 0.58 40
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.

I138V has 46 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
138 0
139 5
135 5
137 5 L137F, L137P,
141 6 V141M,
142 6
136 6
140 6 S140G, S140R, S140R, S140R,
134 7 L134P,
133 9 V133I,
143 9 S143F, S143P, S143Y,
234 10 Q234H, Q234H,
132 10 I132L,
299 10
148 10
145 10
131 10
156 11
144 11 T144A,
300 11 A300T, A300S,
152 11
159 11 M159del,
303 11 L303P,
238 12 M238V, M238L, M238L,
130 12
235 12 I235N,
231 12 R231C, R231H, R231S,
155 12
274 12 I274V,
237 13
160 13 E160del, E160K, E160V,
298 13 S298I, S298N,
149 13
327 13 T327A, T327S, T327S,
323 13
147 14 Q147R,
230 14
151 14
153 14 T153M,
129 14 V129I,
163 14
128 14 A128del,
302 14 A302V, A302E, A302T,
277 15 S277L, S277del, S277P, S277W,
301 15
154 15