KCNQ1 Variant D286H Detail

We estimate the penetrance of LQTS for KCNQ1 D286H is 38%. We are unaware of any observations of this variant in individuals. D286H is not present in gnomAD. D286H 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D286H around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.15 1.0 1 0.818 41
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 7 3 -
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.

D286H has 36 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
286 0
285 4
287 5 A287E, A287T, A287S,
283 7 A283G, A283T,
284 7 E284K,
288 8
281 8 Y281C,
294 8 V294M,
282 9 L282P,
297 9 G297S, G297D, G297R,
322 10 T322M, T322A, T322K,
296 10 F296S, F296L, F296L, F296L,
228 11
295 11
321 11
280 11 V280A, V280E,
324 12
298 12 S298I, S298N,
227 12
289 12
325 12 G325R, G325R, G325E, G325W,
144 13 T144A,
320 13 P320H, P320A, P320S,
224 13 T224M,
323 13
231 14 R231C, R231H, R231S,
302 14 A302V, A302E, A302T,
292 14 G292D,
278 14 Y278H,
223 14
299 14
279 14 F279I,
318 15
290 15 E290K,
146 15 E146K, E146G, E146Q,
326 15