KCNQ1 Variant Y184H Detail

We estimate the penetrance of LQTS for KCNQ1 Y184H is 75%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. Y184H is not present in gnomAD. Y184H has not been functionally characterized. 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 Y184H around 75% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.61 1.0 0 0.944 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
19716085 2009 1 None 1 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.

Y184H has 40 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
184 0 Y184S, Y184C, Y184D, Y184H,
183 4 K183R,
181 5 R181C,
189 5 G189R, G189R, G189E,
193 5 F193L, F193L, F193L,
178 5 A178T, A178del,
182 6
192 7 R192C, R192H,
185 7 V185L, V185L, V185M, V185del,
190 7 R190W, R190Q, R190L,
179 7 G179S,
188 8 W188C, W188C, W188G, W188S,
180 8
186 8 G186R, G186D,
111 9 Y111C,
177 9 S177F,
194 9 A194P, A194T,
191 9
196 9
175 9 L175I,
195 10 R195Q, R195W,
187 10 L187P, L187F,
115 11 E115A, E115G,
199 12 S199A,
244 12
174 12 R174H, R174C, R174L,
116 12
108 12 G108S,
107 13 Q107H, Q107H,
176 13
112 13
197 13 P197L,
171 13
198 13 I198V, I198T,
114 13
173 14
110 14 V110I,
200 14
172 14 V172M, V172E,
243 14 R243H, R243C, R243P, R243S,