KCNH2 Variant G149A Detail

We estimate the penetrance of LQTS for KCNH2 G149A is 4%. This variant was found in a total of 11 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. G149A is present in 11 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 62% of WT with a standard error of 19%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. G149A has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G149A around 4% (0/21).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.115 0.0 0 0.522 0
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 LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 11 7 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

G149A has 31 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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 G149V, G149A,
148 4 R148Q, R148W, R148Y, R148fsX,
150 4 P150L,
147 5 H147X, H147R,
151 5 P151fsX, P151X,
146 7 N146X,
152 7 T152S, T152fsX, T152X, T152I, T152S,
145 8
153 8 S153R, S153R, S153R,
144 8 D144V,
154 8 W154X, W154R, W154R,
143 9
155 9
142 10 A142T,
156 10
141 11 P141S, P141fsX, P141L,
157 11 P157X,
140 11 S140Y,
158 11
139 12 G139R, G139A, G139R,
159 12
138 13
160 13
137 13
161 13
136 14
162 14 T162X,
135 14
163 14
134 15 E134X,
164 15 R164C, R164H,