KCNQ1 Variant S177C Detail

We estimate the penetrance of LQTS for KCNQ1 S177C is 73%. We are unaware of any observations of this variant in individuals. S177C is not present in gnomAD. S177C 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 S177C around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.48 0.991 0 0.894 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
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.

S177C has 50 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
177 0 S177F,
178 4 A178T, A178del,
111 5 Y111C,
107 5 Q107H, Q107H,
179 6 G179S,
110 6 V110I,
180 6
173 6
176 6
175 6 L175I,
108 7 G108S,
174 7 R174H, R174C, R174L,
114 8
190 8 R190W, R190Q, R190L,
115 8 E115A, E115G,
193 8 F193L, F193L, F193L,
181 8 R181C,
112 9
184 9 Y184S, Y184C, Y184D, Y184H,
172 9 V172M, V172E,
106 9
113 10
171 10
170 11
109 11 R109C, R109L,
186 11 G186R, G186D,
116 11
185 11 V185L, V185L, V185M, V185del,
189 11 G189R, G189R, G189E,
104 11 T104A, T104I,
182 12
105 12
183 12 K183R,
194 12 A194P, A194T,
169 13 T169M, T169R,
199 13 S199A,
117 13 P117L,
243 13 R243H, R243C, R243P, R243S,
244 13
196 13
168 14 G168R, G168R, G168R, G168R,
187 14 L187P, L187F,
191 14
188 14 W188C, W188C, W188G, W188S,
122 14 C122Y,
202 14 D202N, D202H,
192 14 R192C, R192H,
198 15 I198V, I198T,
125 15
126 15 H126D,