KCNQ1 Variant Y315C Detail

We estimate the penetrance of LQTS for KCNQ1 Y315C is 90%. This variant was found in a total of 20 carriers in 15 papers or gnomAD, 19 had LQTS. Y315C is not present in gnomAD. Y315C has been functionally characterized in 1 papers. 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y315C around 90% (26/30).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.42 1.0 3 0.979 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
34135346 2021 1 1 None None
32893267 2020 13 None 13 None
30758498 2019 5 None 2 None
27041096 2016 3 None 3 None
24606995 2014 1 None 1 None
24217263 2013 1 None 1 None
23631430 2013 4 None None None
23153844 2012 10 None 1 None
19716085 2009 4 None 4 None
19490272 2009 10 None 10 None
19261104 2008 1 None 1 None
17470695 2007 10 None 10 None
17192539 2006 1 None 1 None
14678125 2003 7 None 7 None
12877697 2003 1 1 None None
LITERATURE, COHORT, AND GNOMAD: - 20 1 19
VARIANT FEATURES ALONE: - 10 3 7 -
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
11087258 Oocytes 0 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
11087258 Oocytes 25 4.0 None None

Y315C 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,