KCNQ1 Variant V207M Detail

We estimate the penetrance of LQTS for KCNQ1 V207M is 4%. This variant was found in a total of 79 carriers in 3 papers or gnomAD, 0 had LQTS. V207M is present in 76 alleles in gnomAD. V207M has been functionally characterized in 2 papers. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V207M around 4% (3/89).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.96 0.869 2 0.733 34
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
22949429 2012 2 2 None None
19841300 2009 2 2 None None
19198868 2009 1 1 None None
LITERATURE, COHORT, AND GNOMAD: - 79 79 0
VARIANT FEATURES ALONE: - 10 7 3 -
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)
20421371 mouse ltk 93 7.1 1.4 1.2
30571187 HEK 88 1.7 None 0.792561724

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)
20421371 mouse ltk None None None
30571187 HEK None None None

V207M has 43 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
207 0 V207M, V207L, V207L, V207L, V207L, V207del,
208 4 A208V,
206 4 V206L,
210 5 M210I, M210I, M210I,
203 6 L203P,
209 6 S209P,
204 6 I204M, I204F,
205 6 V205M,
211 6
212 9
164 9
233 10 L233P,
202 10 D202N, D202H,
168 10 G168R, G168R, G168R, G168R,
213 10
214 10 C214Y,
171 11
201 11 I201del,
200 11
167 12
237 12
165 12 V165M,
230 12
229 12 G229D,
199 12 S199A,
236 12 L236Q, L236R,
225 13 S225L, S225del,
221 13
161 13
160 13 E160del, E160K, E160V,
215 13 V215M, V215G, V215L, V215L,
232 13
226 13 A226V,
240 14 H240R, H240P,
169 14 T169M, T169R,
172 14 V172M, V172E,
163 14
194 14 A194P, A194T,
234 14 Q234H, Q234H,
216 14 G216R,
170 15
166 15 F166V,
198 15 I198V, I198T,