KCNQ1 Variant W304R Detail

We estimate the penetrance of LQTS for KCNQ1 W304R is 78%. This variant was found in a total of 3 carriers in 4 papers or gnomAD, 3 had LQTS. W304R is not present in gnomAD. W304R 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W304R around 78% (10/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-13.62 1.0 -5 0.935 81
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
32470535 2020 1 None 1 None
22949429 2012 1 None 1 None
19841300 2009 1 None 1 None
19490272 2009 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 3 0 3
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.

W304R has 40 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
304 9 W304R, W304R,
302 11 A302V, A302E, A302T,
305 11 W305S, W305L, W305C, W305C, W305R, W305R,
308 11 V308F,
301 11
306 12 G306V, G306R, G306R,
296 12 F296S, F296L, F296L, F296L,
316 12 G316E, G316R, G316R, G316V,
314 12 G314S, G314D, G314C, G314del,
315 12 Y315C, Y315S, Y315N, Y315H, Y315F,
295 12
329 12 A329T,
303 12 L303P,
318 12
307 12 V307L, V307L,
280 12 V280A, V280E,
319 12 V319L, V319L,
317 12 D317N, D317G, D317Y,
309 12 T309I, T309R,
320 13 P320H, P320A, P320S,
277 13 S277L, S277del, S277P, S277W,
313 13
300 13 A300T, A300S,
325 13 G325R, G325R, G325E, G325W,
333 14
141 14 V141M,
284 14 E284K,
276 14 S276del,
311 14 T311A, T311I,
273 14 L273F, L273V, L273R,
310 14 V310I,
330 14
270 14 F270S,
326 14
328 14 I328del,
312 14 T312del, T312I,
322 15 T322M, T322A, T322K,
145 15
298 15 S298I, S298N,
299 15