KCNQ1 Variant A329V Detail

We estimate the penetrance of LQTS for KCNQ1 A329V is 66%. We are unaware of any observations of this variant in individuals. A329V is not present in gnomAD. A329V 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 A329V around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.73 1.0 -2 0.918 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.

A329V has 35 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
328 4 I328del,
331 6
325 6 G325R, G325R, G325E, G325W,
327 6 T327A, T327S, T327S,
324 9
279 9 F279I,
307 10 V307L, V307L,
322 10 T322M, T322A, T322K,
304 11 W304R, W304R,
306 11 G306V, G306R, G306R,
283 11 A283G, A283T,
284 11 E284K,
323 11
305 11 W305S, W305L, W305C, W305C, W305R, W305R,
310 11 V310I,
321 12
278 12 Y278H,
330 12
282 13 L282P,
303 13 L303P,
273 13 L273F, L273V, L273R,
302 13 A302V, A302E, A302T,
277 14 S277L, S277del, S277P, S277W,
309 14 T309I, T309R,
340 14 F340del, F340L, F340L, F340L, F340S,
318 14
276 14 S276del,
313 14
326 14
301 14
300 14 A300T, A300S,
317 14 D317N, D317G, D317Y,
270 15 F270S,
334 15 V334A,
336 15 A336S,