KCNQ1 Variant G314S Detail

We estimate the penetrance of LQTS for KCNQ1 G314S is 90%. This variant was found in a total of 9 carriers in 23 papers or gnomAD, 9 had LQTS. G314S is not present in gnomAD. G314S has been functionally characterized in 5 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G314S around 90% (17/19).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.64 1.0 -1 0.969 98
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
34130155 2021 1 None 1 None
32893267 2020 13 None 13 None
30758498 2019 7 None 5 None
30036649 2018 2 None 2 None
27041096 2016 1 None 1 None
26496715 2016 1 None 1 None
24573873 2007 2 None 2 None
23631430 2013 1 None None None
23153844 2012 19 None 1 None
22949429 2012 4 None 4 None
19841300 2009 4 None 4 None
19716085 2009 7 None 7 None
19490272 2009 19 None 19 None
19348785 2009 None None None None
18752142 2008 1 None 1 RWS
18713323 2008 8 None None None
17470695 2007 8 None 8 None
17192539 2006 4 None 4 None
16922724 2006 1 None 1 None
15028050 2004 1 None 1 None
12566525 2003 1 None 1 None
10220144 1999 2 None 1 None
9799083 1998 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 9 0 9
VARIANT FEATURES ALONE: - 10 2 8 -
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)
9312006 COS 0 None None None
19348785 Oocytes 12 None None None
15051636 Oocytes 0 None None None
16246960 CHO None None None
30571189 HEK 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)
9312006 COS 40 2.3 None 0.930535456
19348785 Oocytes 28 2.3 None None
15051636 Oocytes 25 None None None
16246960 CHO 34 None None None
30571189 HEK 39 4.6 None None

G314S has 19 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
314 4 G314S, G314D, G314C, G314del,
313 7
315 8 Y315C, Y315S, Y315N, Y315H, Y315F,
316 8 G316E, G316R, G316R, G316V,
312 8 T312del, T312I,
308 10 V308F,
309 10 T309I, T309R,
311 11 T311A, T311I,
305 11 W305S, W305L, W305C, W305C, W305R, W305R,
319 12 V319L, V319L,
317 12 D317N, D317G, D317Y,
310 13 V310I,
318 14
306 14 G306V, G306R, G306R,
337 14
307 14 V307L, V307L,
304 14 W304R, W304R,
333 14
320 14 P320H, P320A, P320S,