KCNQ1 Variant G108V Detail

We estimate the penetrance of LQTS for KCNQ1 G108V is 25%. We are unaware of any observations of this variant in individuals. G108V is not present in gnomAD. G108V has not been functionally characterized. 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G108V around 25% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.39 0.79 -2 0.77 24
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 8 2 -
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.

G108V has 36 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
108 0 G108S,
107 5 Q107H, Q107H,
110 5 V110I,
180 5
109 5 R109C, R109L,
112 5
106 6
111 6 Y111C,
105 6
177 7 S177F,
179 8 G179S,
104 8 T104A, T104I,
178 9 A178T, A178del,
113 9
181 9 R181C,
116 9
114 9
115 10 E115A, E115G,
173 11
117 11 P117L,
174 11 R174H, R174C, R174L,
176 12
122 12 C122Y,
184 12 Y184S, Y184C, Y184D, Y184H,
182 12
118 13
175 13 L175I,
119 13 G119R, G119V,
190 13 R190W, R190Q, R190L,
193 14 F193L, F193L, F193L,
121 14
185 14 V185L, V185L, V185M, V185del,
183 14 K183R,
170 15
244 15
172 15 V172M, V172E,