KCNQ1 Variant G179A Detail

We estimate the penetrance of LQTS for KCNQ1 G179A is 59%. We are unaware of any observations of this variant in individuals. G179A is not present in gnomAD. G179A 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G179A around 59% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.53 1.0 -1 0.933 62
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.

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)
30571187 HEK 4 -2.9 None 0.0

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)
30571187 HEK 81 0.4 None 0.939668752

G179A has 37 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
179 0 G179S,
178 4 A178T, A178del,
180 4
177 6 S177F,
185 6 V185L, V185L, V185M, V185del,
181 7 R181C,
190 7 R190W, R190Q, R190L,
184 7 Y184S, Y184C, Y184D, Y184H,
107 7 Q107H, Q107H,
182 7
186 7 G186R, G186D,
111 8 Y111C,
108 8 G108S,
189 9 G189R, G189R, G189E,
176 9
175 9 L175I,
193 9 F193L, F193L, F193L,
183 9 K183R,
104 10 T104A, T104I,
110 10 V110I,
188 10 W188C, W188C, W188G, W188S,
106 11
105 11
173 11
187 11 L187P, L187F,
112 11
174 12 R174H, R174C, R174L,
115 12 E115A, E115G,
192 12 R192C, R192H,
114 13
191 13
109 13 R109C, R109L,
172 13 V172M, V172E,
116 13
194 13 A194P, A194T,
171 14
196 15