KCNQ1 Variant G306R Detail

We estimate the penetrance of LQTS for KCNQ1 G306R is 74%. This variant was found in a total of 1 carriers in 10 papers or gnomAD, 1 had LQTS. G306R is not present in gnomAD. G306R has been functionally characterized in 2 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 G306R around 74% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.78 0.999 -3 0.972 79
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 3 None 3 None
30758498 2019 2 None None None
24667783 2015 1 None 1 None
19716085 2009 1 None 1 None
19716085 2009 1 None 1 None
19490272 2009 2 None 2 None
17470695 2007 2 None 2 None
17192539 2006 1 None 1 None
14678125 2003 17 None 17 None
11351021 2001 None None None None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
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)
10376919 Oocytes None None None
11351021 iPSC-CM 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)
10376919 Oocytes 20 None 1.0 None
11351021 iPSC-CM 18 None None None

G306R has 48 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
277 6 S277L, S277del, S277P, S277W,
302 6 A302V, A302E, A302T,
274 9 I274V,
272 9 G272D, G272S, G272V,
333 10
300 10 A300T, A300S,
329 10 A329T,
299 10
296 10 F296S, F296L, F296L, F296L,
273 11 L273F, L273V, L273R,
276 11 S276del,
269 11 G269D, G269S, G269del,
330 11
275 12 F275del,
279 12 F279I,
336 12 A336S,
320 12 P320H, P320A, P320S,
280 12 V280A, V280E,
278 12 Y278H,
332 12
319 12 V319L, V319L,
304 12 W304R, W304R,
281 12 Y281C,
307 12 V307L, V307L,
271 12
334 12 V334A,
306 13 G306V, G306R, G306R,
328 13 I328del,
298 13 S298I, S298N,
325 13 G325R, G325R, G325E, G325W,
326 13
331 13
310 13 V310I,
335 14 F335L, F335L, F335L,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
313 14
314 14 G314S, G314D, G314C, G314del,
327 14 T327A, T327S, T327S,
297 14 G297S, G297D, G297R,
312 14 T312del, T312I,
282 14 L282P,
141 15 V141M,
266 15 L266P,
235 15 I235N,
315 15 Y315C, Y315S, Y315N, Y315H, Y315F,
338 15 S338F,
268 15 I268V, I268S,
284 15 E284K,