KCNQ1 Variant G216R Detail

We estimate the penetrance of LQTS for KCNQ1 G216R is 74%. This variant was found in a total of 5 carriers in 1 papers or gnomAD, 5 had LQTS. G216R is not present in gnomAD. G216R 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G216R around 74% (11/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.87 0.995 -2 0.932 70
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
9272155 1997 5 None 5 None
LITERATURE, COHORT, AND GNOMAD: - 5 0 5
VARIANT FEATURES ALONE: - 10 4 6 -
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.

G216R has 38 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
216 0 G216R,
215 4 V215M, V215G, V215L, V215L,
217 4
213 5
222 5
214 6 C214Y,
218 6
219 6 G219E,
212 7
157 7 F157C,
221 8
226 8 A226V,
211 9
223 9
161 10
225 10 S225L, S225del,
220 10 Q220K,
210 10 M210I, M210I, M210I,
209 11 S209P,
227 11
230 11
160 11 E160del, E160K, E160V,
153 11 T153M,
224 11 T224M,
154 12
208 12 A208V,
156 12
229 13 G229D,
164 13
158 14
228 14
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
155 14
162 14 V162M,
152 15
233 15 L233P,
159 15 M159del,
231 15 R231C, R231H, R231S,