KCNH2 Variant P141L Detail

We estimate the penetrance of LQTS for KCNH2 P141L is 1%. This variant was found in a total of 111 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. P141L is present in 111 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 135% of WT with a standard error of 21%; 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. P141L 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 P141L around 1% (0/121).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.894 0.0 -2 0.608 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: - 111 81 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.

P141L 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
141 0 P141L, P141fsX, P141S,
140 4 S140Y,
142 4 A142T,
139 5 G139R, G139R, G139A,
143 5
138 7
144 7 D144V,
137 8
145 8
136 8
146 8 N146X,
135 9
147 9 H147X, H147R,
134 10 E134X,
148 10 R148Q, R148fsX, R148W, R148Y,
133 11 M133T,
149 11 G149A, G149V,
132 11 V132X,
150 11 P150L,
131 12 V131L, V131fsX, V131L,
151 12 P151fsX, P151X,
130 13 E130K,
152 13 T152fsX, T152X, T152I, T152S, T152S,
129 13 F129C,
153 13 S153R, S153R, S153R,
128 14 N128S,
154 14 W154R, W154R, W154X,
127 14
155 14
126 15
156 15