KCNQ1 Variant H258P Detail

We estimate the penetrance of LQTS for KCNQ1 H258P is 73%. This variant was found in a total of 20 carriers in 5 papers or gnomAD, 16 had LQTS. H258P is not present in gnomAD. H258P 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H258P around 73% (21/30).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.72 1.0 -4 0.948 69
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
30758498 2019 5 None 3 None
29439887 2018 5 3 2 None
22708720 2013 12 1 11 None
17192539 2006 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 20 4 16
VARIANT FEATURES ALONE: - 10 5 5 -
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.

H258P has 21 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
260 11
358 12 K358T,
259 12 R259C, R259H, R259L, R259G,
250 12 L250H, L250P,
254 12 V254M, V254L, V254L,
352 12
349 12 S349W,
265 13 T265I,
251 13 L251P, L251Q,
264 13
348 13
263 13
253 14 S253A, S253P,
257 14 I257V,
353 14 L353P,
350 14 G350V, G350R, G350R, G350W,
252 14 G252R,
345 14 G345R, G345R, G345A,
255 15
355 15
351 15 F351L, F351L, F351L, F351S,