KCNQ1 Variant Y315H Detail

We estimate the penetrance of LQTS for KCNQ1 Y315H is 85%. This variant was found in a total of 2 carriers in 2 papers or gnomAD, 2 had LQTS. Y315H is not present in gnomAD. Y315H 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 Y315H around 85% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.7 1.0 0 0.957 95
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 1 None 1 None
24667783 2015 1 None 1 None
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.

Y315H has 16 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
314 7 G314S, G314D, G314C, G314del,
315 9 Y315C, Y315S, Y315N, Y315H, Y315F,
316 9 G316E, G316R, G316R, G316V,
313 10
308 11 V308F,
312 11 T312del, T312I,
319 12 V319L, V319L,
309 12 T309I, T309R,
317 12 D317N, D317G, D317Y,
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
311 14 T311A, T311I,
318 14
320 14 P320H, P320A, P320S,
304 15 W304R, W304R,
310 15 V310I,
306 15 G306V, G306R, G306R,