KCNQ1 Variant H126D Detail

We estimate the penetrance of LQTS for KCNQ1 H126D is 79%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. H126D is not present in gnomAD. H126D 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H126D around 79% (9/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.85 0.999 2 0.915 84
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 2 None 2 None
LITERATURE, COHORT, AND GNOMAD: - 2 0 2
VARIANT FEATURES ALONE: - 10 3 7 -
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.

H126D has 49 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
126 0 H126D,
125 4
129 6 V129I,
122 6 C122Y,
123 6
128 7 A128del,
124 7
113 7
241 7 V241F, V241I, V241G,
114 7
127 7 F127L, F127L, F127L,
117 7 P117L,
243 8 R243H, R243C, R243P, R243S,
130 8
170 9
115 9 E115A, E115G,
121 9
119 9 G119R, G119V,
174 10 R174H, R174C, R174L,
131 10
240 10 H240R, H240P,
120 10 W120C, W120C,
132 11 I132L,
242 11 D242N, D242Y,
118 11
167 11
166 11 F166V,
133 11 V133I,
112 11
110 12 V110I,
244 12
116 12
111 12 Y111C,
238 13 M238V, M238L, M238L,
134 13 L134P,
173 13
202 13 D202N, D202H,
198 13 I198V, I198T,
239 13
237 14
163 14
245 14 G245V,
246 14
169 14 T169M, T169R,
171 14
168 14 G168R, G168R, G168R, G168R,
267 14 Y267C,
247 15 T247I,
177 15 S177F,