KCNQ1 Variant A336D Detail

We estimate the penetrance of LQTS for KCNQ1 A336D is 65%. We are unaware of any observations of this variant in individuals. A336D is not present in gnomAD. A336D 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A336D around 65% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.91 0.996 -1 0.939 71
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.

A336D has 32 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
276 9 S276del,
275 12 F275del,
307 12 V307L, V307L,
251 12 L251P, L251Q,
269 12 G269D, G269S, G269del,
266 12 L266P,
270 12 F270S,
330 13
337 13
312 13 T312del, T312I,
334 13 V334A,
273 13 L273F, L273V, L273R,
336 13 A336S,
279 13 F279I,
306 13 G306V, G306R, G306R,
265 14 T265I,
341 14 A341V, A341E,
333 14
338 14 S338F,
310 14 V310I,
331 14
280 14 V280A, V280E,
340 14 F340del, F340L, F340L, F340L, F340S,
329 14 A329T,
332 14
272 14 G272D, G272S, G272V,
262 14 L262P, L262R, L262V,
311 15 T311A, T311I,
252 15 G252R,
248 15 W248C, W248C, W248R, W248R,
309 15 T309I, T309R,
278 15 Y278H,