KCNQ1 Variant P320A Detail

We estimate the penetrance of LQTS for KCNQ1 P320A is 74%. This variant was found in a total of 1 carriers in 3 papers or gnomAD, 1 had LQTS. P320A is not present in gnomAD. P320A has been functionally characterized in 1 papers. 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 P320A around 74% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.35 1.0 2 0.931 77
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
32893267 2020 1 None 1 None
19540844 2010 None None None None
17192539 2006 2 None 2 None
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19540844 Oocytes 0 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19540844 Oocytes 23 3.3 None None

P320A has 38 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 9 I328del,
283 9 A283G, A283T,
324 9
326 9
304 9 W304R, W304R,
323 10
325 11 G325R, G325R, G325E, G325W,
322 11 T322M, T322A, T322K,
318 12
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
301 12
295 12
319 12 V319L, V319L,
282 12 L282P,
279 12 F279I,
306 13 G306V, G306R, G306R,
296 13 F296S, F296L, F296L, F296L,
332 13
320 13 P320H, P320A, P320S,
331 13
302 13 A302V, A302E, A302T,
307 13 V307L, V307L,
285 13
286 13
315 13 Y315C, Y315S, Y315N, Y315H, Y315F,
327 13 T327A, T327S, T327S,
330 13
300 14 A300T, A300S,
314 14 G314S, G314D, G314C, G314del,
316 14 G316E, G316R, G316R, G316V,
303 14 L303P,
309 14 T309I, T309R,
278 14 Y278H,
293 14 R293C, R293H,
290 14 E290K,
280 15 V280A, V280E,
313 15
317 15 D317N, D317G, D317Y,