KCNQ1 Variant G119D Detail

We estimate the penetrance of LQTS for KCNQ1 G119D is 86%. We are unaware of any observations of this variant in individuals. G119D is not present in gnomAD. G119D 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G119D around 86% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.34 0.787 2 0.905 99
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.

G119D has 25 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
119 0 G119R, G119V,
118 4
122 4 C122Y,
120 6 W120C, W120C,
117 6 P117L,
121 6
123 7
113 8
124 8
112 9
126 9 H126D,
116 10
125 11
114 11
109 12 R109C, R109L,
127 12 F127L, F127L, F127L,
115 12 E115A, E115G,
110 12 V110I,
111 13 Y111C,
108 13 G108S,
128 14 A128del,
243 14 R243H, R243C, R243P, R243S,
241 15 V241F, V241I, V241G,
129 15 V129I,
244 15