KCNQ1 Variant T322M Detail

We estimate the penetrance of LQTS for KCNQ1 T322M is 83%. This variant was found in a total of 31 carriers in 11 papers or gnomAD, 26 had LQTS. T322M is present in 1 alleles in gnomAD. T322M 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 T322M around 83% (33/41).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.57 1.0 3 0.968 88
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 13 None 13 None
30758498 2019 10 None None None
30758498 2019 4 None None None
26496715 2016 5 None 5 None
23631430 2013 1 None None None
23092362 2012 13 None None None
21956039 2011 3 None 3 None
19716085 2009 4 None 4 None
19490272 2009 2 None 2 None
18400097 2008 5 4 1 None
17470695 2007 2 None 2 None
LITERATURE, COHORT, AND GNOMAD: - 31 5 26
VARIANT FEATURES ALONE: - 10 3 7 -
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)
23092362 HEK 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)
23092362 HEK 20 12.0 1.0 None

T322M has 33 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
322 0 T322M, T322A, T322K,
325 5 G325R, G325R, G325E, G325W,
324 5
284 5 E284K,
321 5
326 5
323 6
283 6 A283G, A283T,
287 7 A287E, A287T, A287S,
327 8 T327A, T327S, T327S,
328 9 I328del,
286 10
288 10
282 10 L282P,
329 10 A329T,
285 11
279 12 F279I,
290 12 E290K,
330 12
304 13 W304R, W304R,
301 13
318 13
276 13 S276del,
317 14 D317N, D317G, D317Y,
331 14
278 14 Y278H,
300 14 A300T, A300S,
295 14
296 14 F296S, F296L, F296L, F296L,
332 14
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
302 15 A302V, A302E, A302T,
298 15 S298I, S298N,