KCNQ1 Variant A287G Detail

We estimate the penetrance of LQTS for KCNQ1 A287G is 26%. We are unaware of any observations of this variant in individuals. A287G is not present in gnomAD. A287G has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A287G around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.34 0.99 1 0.773 28
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
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.

A287G has 25 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
287 0 A287E, A287T, A287S,
288 4
286 5
284 5 E284K,
285 7
322 7 T322M, T322A, T322K,
283 7 A283G, A283T,
281 9 Y281C,
320 10 P320H, P320A, P320S,
280 10 V280A, V280E,
282 11 L282P,
325 11 G325R, G325R, G325E, G325W,
324 11
323 12
293 14 R293C, R293H,
328 14 I328del,
299 14
228 15
279 15 F279I,
277 15 S277L, S277del, S277P, S277W,
321 15
144 15 T144A,
317 15 D317N, D317G, D317Y,
295 15
294 15 V294M,