KCNH2 Variant G139R Detail

We estimate the penetrance of LQTS for KCNH2 G139R is 5%. This variant was found in a total of 6 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. G139R is present in 6 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 125% of WT with a standard error of 20%; 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. G139R 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 G139R around 5% (0/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.768 0.003 2 0.425 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: - 6 2 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.

G139R 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
139 0 G139R, G139R, G139A,
138 4
140 4 S140Y,
137 5
141 5 P141L, P141fsX, P141S,
136 7
142 7 A142T,
135 8
143 8
134 8 E134X,
144 8 D144V,
133 9 M133T,
145 9
132 10 V132X,
146 10 N146X,
131 11 V131L, V131fsX, V131L,
147 11 H147X, H147R,
130 11 E130K,
148 11 R148Q, R148fsX, R148W, R148Y,
129 12 F129C,
149 12 G149A, G149V,
128 13 N128S,
150 13 P150L,
127 13
151 13 P151fsX, P151X,
126 14
152 14 T152fsX, T152X, T152I, T152S, T152S,
125 14
153 14 S153R, S153R, S153R,
124 15 M124T, M124R,
154 15 W154R, W154R, W154X,