KCNQ1 Variant A178P Detail

We estimate the penetrance of LQTS for KCNQ1 A178P is 72%. We are unaware of any observations of this variant in individuals. A178P is not present in gnomAD. A178P 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 A178P around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.19 1.0 2 0.905 78
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
19490272 2009 5 None 5 None
17470695 2007 5 None 5 None
14678125 2003 3 None 3 None
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
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)
9323054 Oocytes 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)
9323054 Oocytes 25 10.0 None None

A178P has 46 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
178 0 A178T, A178del,
179 4 G179S,
177 4 S177F,
180 5
184 5 Y184S, Y184C, Y184D, Y184H,
190 5 R190W, R190Q, R190L,
111 6 Y111C,
181 6 R181C,
193 6 F193L, F193L, F193L,
175 7 L175I,
189 7 G189R, G189R, G189E,
185 8 V185L, V185L, V185M, V185del,
107 8 Q107H, Q107H,
186 8 G186R, G186D,
176 8
108 9 G108S,
183 9 K183R,
182 9
174 9 R174H, R174C, R174L,
115 9 E115A, E115G,
110 9 V110I,
173 9
114 10
194 10 A194P, A194T,
112 10
188 11 W188C, W188C, W188G, W188S,
172 11 V172M, V172E,
191 11
192 11 R192C, R192H,
187 11 L187P, L187F,
171 11
116 11
196 12
106 12
199 12 S199A,
244 13
104 13 T104A, T104I,
170 13
105 13
113 13
109 13 R109C, R109L,
195 13 R195Q, R195W,
243 14 R243H, R243C, R243P, R243S,
198 14 I198V, I198T,
117 15 P117L,
202 15 D202N, D202H,